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Chen SY, Zhang YL, Li XR, Wang JR, Li KP, Wan S, Yang JW, Wang H, Cao JL, Wang CY, Fan XP, Fu SJ, Ding LY, Che TJ, Yang L. BIN1 inhibited tumor growth, metastasis and stemness by ALDH1/NOTCH pathway in bladder carcinoma. Hereditas 2025; 162:29. [PMID: 40016843 PMCID: PMC11866615 DOI: 10.1186/s41065-025-00384-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/01/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Bladder cancer (BLCA) represents one of the most prevalent urological malignancies worldwide. Bridging integrator 1 (BIN1), a well-characterized tumor suppressor that interacts with and inhibits oncogenic Myc transcription factors, has demonstrated crucial roles in various cancer types. However, its specific functions and underlying molecular mechanisms in BLCA development and progression remain poorly understood. This study aims to elucidate the role of BIN1 in regulating BLCA cell proliferation, metastasis, and cancer stem cell properties. METHODS Using urinary proteomics analysis, we identified BIN1 as a significantly dysregulated protein in BLCA. The clinical significance of BIN1 was further validated through comprehensive analyses of public databases. BIN1 expression levels defined distinct molecular and immunological subtypes of BLCA. Through proteomic profiling of BIN1-overexpressing UMUC3 cells and corresponding controls, we identified ALDH1 as a key downstream effector in the BIN1-regulated ALDH1/NOTCH signaling axis. We employed multiple experimental approaches, including Western blot analysis, quantitative RT-PCR, immunofluorescence staining, wound healing assays, transwell migration assays, colony formation assays, tumor sphere formation assays, flow cytometry, CCK8 proliferation assays, and cell transfection experiments. RESULTS We observed significant downregulation of BIN1 in both BLCA tissues and cell lines compared to normal adjacent tissues and SV-HUC-1 cells, respectively. BIN1 overexpression inhibited cancer cell proliferation by promoting apoptosis and suppressed epithelial-mesenchymal transition (EMT), thereby reducing local invasion and distant metastasis. Additionally, BIN1 regulated cancer stem cell properties through modulation of ALDH1 expression, with NOTCH2 acting as a crucial downstream mediator of ALDH1 signaling. CONCLUSION Our findings demonstrate that BIN1 functions as a tumor suppressor in BLCA and suggest its potential utility as both a diagnostic biomarker and therapeutic target for BLCA treatment.
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Affiliation(s)
- Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Ya-Long Zhang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Xiao-Ran Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Ji-Rong Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Kun-Peng Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Shun Wan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Jian-Wei Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Hao Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Chen-Yang Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Xin-Peng Fan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Sheng-Jun Fu
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Li-Yun Ding
- School of Physical Science and Technology, Lanzhou University, Lanzhou, China
| | - Tuan-Jie Che
- Baiyuan Company for Gene Technology, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China.
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Harris DE, Kim JJ, Stern SR, Vicars HM, Matias NR, Gallicchio L, Baker CC, Fuller MT. An RNA binding regulatory cascade controls the switch from proliferation to differentiation in the Drosophila male germ cell lineage. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.09.06.611673. [PMID: 39282418 PMCID: PMC11398533 DOI: 10.1101/2024.09.06.611673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
The switch from precursor cell proliferation to onset of differentiation in adult stem cell lineages must be carefully regulated to produce sufficient progeny to maintain and repair tissues, yet prevent overproliferation that may enable oncogenesis. In the Drosophila male germ cell lineage, spermatogonia produced by germ line stem cells undergo a limited number of transit amplifying mitotic divisions before switching to the spermatocyte program that sets up meiosis and eventual spermatid differentiation. The number of transit amplifying divisions is set by accumulation of the bag-of-marbles (Bam) protein to a critical threshold. In bam mutants, spermatogonia proliferate through several extra rounds of mitosis then die without becoming spermatocytes. Here we show that a key role of Bam for the mitosis to differentiation switch is repressing expression of Held Out Wings (how), homolog of mammalian Quaking. Knockdown of how in germ cells was sufficient to allow spermatogonia mutant for bam or its partner benign gonial cell neoplasm (bgcn) to differentiate, while forced expression of nuclear-targeted How protein in spermatogonia wild-type for bam resulted in continued proliferation at the expense of differentiation. Our findings suggest that Bam targets how RNA for degradation by acting as an adapter to recruit the CCR4-NOT deadenylation complex via binding its subunit, Caf40. As How is itself an RNA binding protein with roles in RNA processing, our findings reveal that the switch from proliferation to meiosis and differentiation in the Drosophila male germ line adult stem cell lineage is regulated by a cascade of RNA-binding proteins.
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Affiliation(s)
- Devon E. Harris
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jongmin J. Kim
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Current address: Department of Biomedical Sciences, Cornell University, Ithaca NY, 14853, USA
| | - Sarah R. Stern
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hannah M. Vicars
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Neuza R. Matias
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Lorenzo Gallicchio
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Catherine C. Baker
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Margaret T. Fuller
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Zhu X, Xu M, Portal C, Lin Y, Ferdinand A, Peng T, Morrisey EE, Dlugosz AA, Castellano JM, Lee V, Seykora JT, Wong SY, Iomini C, Millar SE. Identification of Meibomian gland stem cell populations and mechanisms of aging. Nat Commun 2025; 16:1663. [PMID: 39955307 PMCID: PMC11830078 DOI: 10.1038/s41467-025-56907-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 02/05/2025] [Indexed: 02/17/2025] Open
Abstract
Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identify markers for stem cell populations that maintain distinct regions of the gland and uncover Hedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we show that human Meibomian gland carcinoma exhibits increased Hh signaling. Aged glands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.
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Affiliation(s)
- Xuming Zhu
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Mingang Xu
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Celine Portal
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France
| | - Yvonne Lin
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Alyssa Ferdinand
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Tien Peng
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Edward E Morrisey
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Andrzej A Dlugosz
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Joseph M Castellano
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Nash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Vivian Lee
- Department of Ophthalmology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - John T Seykora
- Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sunny Y Wong
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Carlo Iomini
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
| | - Sarah E Millar
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Lica JJ, Jakóbkiewicz-Banecka J, Hellmann A. In Vitro models of leukemia development: the role of very small leukemic stem-like cells in the cellular transformation cascade. Front Cell Dev Biol 2025; 12:1463807. [PMID: 39830209 PMCID: PMC11740207 DOI: 10.3389/fcell.2024.1463807] [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: 07/15/2024] [Accepted: 11/28/2024] [Indexed: 01/22/2025] Open
Abstract
Recent experimental findings indicate that cancer stem cells originate from transformed very small embryonic-like stem cells. This finding represents an essential advancement in uncovering the processes that drive the onset and progression of cancer. In continuously growing cell lines, for the first time, our team's follow-up research on leukemia, lung cancer, and healthy embryonic kidney cells revealed stages that resembles very small precursor stem cells. This review explores the origin of leukemic stem-like cells from very small leukemic stem-like cells establish from transformed very small embryonic-like stem cells. We explore theoretical model of acute myeloid leukemia initiation and progresses through various stages, as well basing the HL60 cell line, present its hierarchical stage development in vitro, highlighting the role of these very small precursor primitive stages. We also discuss the potential implications of further research into these unique cellular stages for advancing leukemia and cancer treatment and prevention.
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Affiliation(s)
- Jan Jakub Lica
- Department Medical Biology and Genetics, Faculty of Biology, University of Gdansk, Gdansk, Poland
- Department Health Science; Powiśle University, Gdańsk, Poland
| | | | - Andrzej Hellmann
- Department of Hematology and Transplantology, Faculty of Medicine, Medical University of Gdansk, Gdańsk, Poland
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Kabak EC, Foo SL, Rafaeva M, Martin I, Bentires-Alj M. Microenvironmental Regulation of Dormancy in Breast Cancer Metastasis: "An Ally that Changes Allegiances". ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:373-395. [PMID: 39821034 DOI: 10.1007/978-3-031-70875-6_18] [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: 01/19/2025]
Abstract
Breast cancer remission after treatment is sometimes long-lasting, but in about 30% of cases, there is a relapse after a so-called dormant state. Cellular cancer dormancy, the propensity of disseminated tumor cells (DTCs) to remain in a nonproliferative state for an extended period, presents an opportunity for therapeutic intervention that may prevent reawakening and the lethal consequences of metastatic outgrowth. Therefore, identification of dormant DTCs and detailed characterization of cancer cell-intrinsic and niche-specific [i.e., tumor microenvironment (TME) mediated] mechanisms influencing dormancy in different metastatic organs are of great importance in breast cancer. Several microenvironmental drivers of DTC dormancy in metastatic organs, such as the lung, bone, liver, and brain, have been identified using in vivo models and/or in vitro three-dimensional culture systems. TME induction and persistence of dormancy in these organs are mainly mediated by signals from immune cells, stromal cells, and extracellular matrix components of the TME. Alterations of the TME have been shown to reawaken dormant DTCs. Efforts to capitalize on these findings often face translational challenges due to limited availability of representative patient samples and difficulty in designing dormancy-targeting clinical trials. In this chapter, we discuss current approaches to identify dormant DTCs and provide insights into cell-extrinsic (i.e., TME) mechanisms driving breast cancer cell dormancy in distant organs.
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Affiliation(s)
- Evrim Ceren Kabak
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Sok Lin Foo
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland
| | - Maria Rafaeva
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Mohamed Bentires-Alj
- Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland.
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Campos J, Sampaio-Marques B, Santos D, Barata-Antunes S, Ribeiro M, Serra SC, Pinho TS, Canto-Gomes J, Marote A, Cortez M, Silva NA, Michael-Titus AT, Salgado AJ. Lipid Priming of Adipose Mesenchymal Stromal Cells with Docosahexaenoic Acid: Impact on Cell Differentiation, Senescence and the Secretome Neuroregulatory Profile. Tissue Eng Regen Med 2025; 22:113-128. [PMID: 39495459 PMCID: PMC11711600 DOI: 10.1007/s13770-024-00679-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/23/2024] [Accepted: 10/02/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Priming strategies that improve the functionality of MSCs may be required to address issues limiting successful clinical translation of MSC therapies. For conditions requiring high trophic support such as brain and spinal cord injuries, priming MSCs to produce higher levels of trophic factors may be instrumental to facilitate translation of current MSC therapies. We developed and tested a novel molecular priming paradigm using docosahexaenoic acid (DHA) to prime adipose tissue-derived mesenchymal stromal cells (ASCs) to enhance the secretome neuroregulatory potential. METHODS Comprehensive dose-response and time-course assays were carried to determine an optimal priming protocol. Secretome total protein measurements were taken in association with cell viability, density and morphometric assessments. Cell identity and differentiation capacity were studied by flow cytometry and lineage-specific markers. Cell growth was assessed by trypan-blue exclusion and senescence was probed over time using SA-β-gal, morphometry and gene expression. Secretomes were tested for their ability to support differentiation and neurite outgrowth of human neural progenitor cells (hNPCs). Neuroregulatory proteins in the secretome were identified using multiplex membrane arrays. RESULTS Priming with 40 µM DHA for 72 h significantly enhanced the biosynthetic capacity of ASCs, producing a secretome with higher protein levels and increased metabolic viability. DHA priming enhanced ASCs adipogenic differentiation and adapted their responses to replicative senescence induction. Furthermore, priming increased concentrations of neurotrophic factors in the secretome promoting neurite outgrowth and modulating the differentiation of hNPCs. CONCLUSIONS These results provide proof-of-concept evidence that DHA priming is a viable strategy to improve the neuroregulatory profile of ASCs.
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Affiliation(s)
- Jonas Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Diogo Santos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Sandra Barata-Antunes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Miguel Ribeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Sofia C Serra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Tiffany S Pinho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - João Canto-Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana Marote
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Margarida Cortez
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno A Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Adina T Michael-Titus
- Centre for Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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Khiabani NA, Doustvandi MA, Story D, Nobari SA, Hajizadeh M, Petersen R, Dunbar G, Rossignol J. Glioblastoma therapy: State of the field and future prospects. Life Sci 2024; 359:123227. [PMID: 39537100 DOI: 10.1016/j.lfs.2024.123227] [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: 06/25/2024] [Revised: 09/03/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma (GB) is a cancerous brain tumor that originates from glial cells and leads to thousands of deaths each year and a five-year survival of only 6.8 %. Treatments for GB include surgery, chemotherapy, radiation, and immunotherapy. GB is an incurable fatal disease, necessitating the development of innovative strategies to find a developing effective therapy. Genetic therapies may be crucial in treating GB by identifying the mutations and amplifications of multiple genes, which drive its proliferation and spread. Use of small interfering RNAs (siRNAs) provides a novel technology used to suppress the genes associated with disease, which forms a basis for targeted therapy in GB and its stem cell population, which are recognized for their ability to develop resistance to chemotherapy and tumorigenic capabilities. This review examines the use of siRNAs in GB, emphasizing their effectiveness in suppressing key oncogenes and signaling pathways associated with tumor development, invasion, stemness, and resistance to standard treatments. siRNA-based gene silencing is a promising approach for developing targeted therapeutics against GB and associated stem cell populations, potentially enhancing patient outcomes and survival rates in this devastating disease.
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Affiliation(s)
- Nadia Allahyarzadeh Khiabani
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, USA; Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | | | - Darren Story
- Department of Psychology, Saginaw Valley State University, University Center, MI 48710, USA
| | | | | | - Robert Petersen
- College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | - Gary Dunbar
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, USA; Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, USA; Department of Psychology, Central Michigan University, Mount Pleasant, MI, USA
| | - Julien Rossignol
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, USA; Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI, USA.
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Zeng P, Shu LZ, Zhou YH, Huang HL, Wei SH, Liu WJ, Deng H. Stem Cell Division and Its Critical Role in Mammary Gland Development and Tumorigenesis: Current Progress and Remaining Challenges. Stem Cells Dev 2024; 33:449-467. [PMID: 38943275 DOI: 10.1089/scd.2024.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2024] Open
Abstract
The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells and that these stem cells participate in two division modes: symmetric cell division (SCD) and asymmetrical cell division (ACD). Although both of these modes are key to the process of breast development and their imbalance is closely associated with the onset of BC, the molecular mechanisms underlying these phenomena deserve in-depth exploration. In this review, we first outline the molecular mechanisms governing ACD/SCD and analyze the role of ACD/SCD in various stages of breast development. We describe that the changes in telomerase activity, the role of polar proteins, and the stimulation of ovarian hormones subsequently lead to two distinct consequences: breast development or carcinogenesis. Finally, gene mutations, abnormalities in polar proteins, modulation of signal-transduction pathways, and alterations in the microenvironment disrupt the balance of BC stem cell division modes and cause BC. Important regulatory factors such as mammalian Inscuteable mInsc, Numb, Eya1, PKCα, PKCθ, p53, and IL-6 also play significant roles in regulating pathways of ACD/SCD and may constitute key targets for future research on stem cell division, breast development, and tumor therapy.
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MESH Headings
- Humans
- Female
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- Breast Neoplasms/genetics
- Animals
- Mammary Glands, Human/growth & development
- Mammary Glands, Human/pathology
- Mammary Glands, Human/cytology
- Mammary Glands, Human/metabolism
- Carcinogenesis/pathology
- Carcinogenesis/metabolism
- Carcinogenesis/genetics
- Stem Cells/metabolism
- Stem Cells/cytology
- Cell Division
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Mammary Glands, Animal/growth & development
- Mammary Glands, Animal/cytology
- Mammary Glands, Animal/pathology
- Mammary Glands, Animal/metabolism
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Signal Transduction
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Affiliation(s)
- Peng Zeng
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Lin-Zhen Shu
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yu-Hong Zhou
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Hai-Lin Huang
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Shu-Hua Wei
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Wen-Jian Liu
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Huan Deng
- Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- The Fourth Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Tumor Immunology Institute, Nanchang University, Nanchang, China
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China
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9
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Zhu X, Xu M, Portal C, Lin Y, Ferdinand A, Peng T, Morrisey EE, Dlugosz AA, Castellano JM, Lee V, Seykora JT, Iomini C, Millar SE. Identification of Meibomian gland stem cell populations and mechanisms of aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.09.607015. [PMID: 39149265 PMCID: PMC11326261 DOI: 10.1101/2024.08.09.607015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identified markers for stem cell populations that maintain distinct regions of the gland and uncovered Hh signaling as a key regulator of stem cell proliferation. Consistent with this, human Meibomian gland carcinoma exhibited increased Hh signaling. Aged glands displayed decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.
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Affiliation(s)
- Xuming Zhu
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mingang Xu
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Celine Portal
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Yvonne Lin
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Alyssa Ferdinand
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Tien Peng
- Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Edward E. Morrisey
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Andrzej A. Dlugosz
- Department of Dermatology and the Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Joseph M. Castellano
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Nash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Vivian Lee
- Department of Ophthalmology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - John T. Seykora
- Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Carlo Iomini
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Sarah E Millar
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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10
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Vidaurre V, Song A, Li T, Ku WL, Zhao K, Qian J, Chen X. The Drosophila histone methyltransferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation. Development 2024; 151:dev202729. [PMID: 39007366 PMCID: PMC11369688 DOI: 10.1242/dev.202729] [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: 01/25/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase Set1 regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of Set1 results in temporally progressive defects, arising as germ cell loss and developing into overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage non-cell-autonomously. Additionally, wild-type Set1, but not the catalytically inactive Set1, rescues the Set1 knockdown phenotypes, highlighting the functional importance of the methyltransferase activity of Set1. Further, RNA-sequencing experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene Stat92E and the BMP pathway gene Mad, which are upregulated upon Set1 knockdown. Genetic interaction assays support the functional relationships between Set1 and JAK-STAT or BMP pathways, as both Stat92E and Mad mutations suppress the Set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The phenotype of germ cell loss followed by over-proliferation when inhibiting a histone methyltransferase also raises concerns about using their inhibitors in cancer therapy.
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Affiliation(s)
- Velinda Vidaurre
- Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - Annabelle Song
- Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - Taibo Li
- Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - Wai Lim Ku
- Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20814, USA
| | - Keji Zhao
- Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20814, USA
| | - Jiang Qian
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Xin Chen
- Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA
- Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA
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11
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Radak M, Fallahi H. Cell-cell communication in stem cells and cancer: Alone but in touch. Fundam Clin Pharmacol 2024; 38:479-488. [PMID: 38228866 DOI: 10.1111/fcp.12982] [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: 05/03/2023] [Revised: 11/27/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024]
Abstract
BACKGROUND Cellular communication and signaling pathways are fundamental regulators of stem cell and cancer cell behaviors. This review explores the intricate interplay of these pathways in governing cellular behaviors, focusing on their implications for diseases, particularly cancer. OBJECTIVES This comprehensive review aims to elucidate the significance of cellular signaling pathways in regulating the behavior of stem cells and cancer cells. It delves into the alterations in these pathways, their impact on cell fate, and their implications for developing diseases, notably cancer. The objective is to underscore the importance of understanding these signaling pathways for developing targeted therapeutic strategies. METHODS The review critically analyzes existing literature and research findings concerning the roles of signaling pathways in stem cell behavior regulation, emphasizing their parallels and disparities in cancer cells. It synthesizes information on both direct and indirect modes of cell communication to delineate the complexity of signaling networks. RESULTS Direct and indirect modes of cell communication intricately regulate the complex signaling pathways governing stem cell behaviors, influencing differentiation potential and tissue regeneration. Alterations in these pathways significantly impact stem cell fate, contributing to disease pathogenesis, including cancer. Understanding these signaling cascades offers insights into developing targeted therapies, particularly cancer treatment. CONCLUSION Understanding the regulation of signaling pathways in stem cells and the specialized subset of cancer stem cells holds promise for innovative therapeutic approaches. By targeting aberrant signaling pathways, tailored interventions may improve treatment outcomes. This review underscores the critical role of signaling pathways in cellular behaviors, offering a pathway toward developing novel, more effective therapies for diverse diseases and disorders.
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Affiliation(s)
- Mehran Radak
- Department of Biology, School of Sciences, Razi University, Kermanshah, Iran
| | - Hossein Fallahi
- Department of Biology, School of Sciences, Razi University, Kermanshah, Iran
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12
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Lv X, Yang L, Xie Y, Momeni MR. Non-coding RNAs and exosomal non-coding RNAs in lung cancer: insights into their functions. Front Cell Dev Biol 2024; 12:1397788. [PMID: 38859962 PMCID: PMC11163066 DOI: 10.3389/fcell.2024.1397788] [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: 03/08/2024] [Accepted: 05/02/2024] [Indexed: 06/12/2024] Open
Abstract
Lung cancer is the second most common form of cancer worldwide Research points to the pivotal role of non-coding RNAs (ncRNAs) in controlling and managing the pathology by controlling essential pathways. ncRNAs have all been identified as being either up- or downregulated among individuals suffering from lung cancer thus hinting that they may play a role in either promoting or suppressing the spread of the disease. Several ncRNAs could be effective non-invasive biomarkers to diagnose or even serve as effective treatment options for those with lung cancer, and several molecules have emerged as potential targets of interest. Given that ncRNAs are contained in exosomes and are implicated in the development and progression of the malady. Herein, we have summarized the role of ncRNAs in lung cancer. Moreover, we highlight the role of exosomal ncRNAs in lung cancer.
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Affiliation(s)
- Xiaolong Lv
- Department of Cardiothoracic Surgery, The People’s Hospital of Changshou, Chongqing, China
| | - Lei Yang
- Department of Cardiothoracic Surgery, The People’s Hospital of Tongliang District, Chongqing, China
| | - Yunbo Xie
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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13
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Sireci S, Kocagöz Y, Alkiraz AS, Güler K, Dokuzluoglu Z, Balcioglu E, Meydanli S, Demirler MC, Erdogan NS, Fuss SH. HB-EGF promotes progenitor cell proliferation and sensory neuron regeneration in the zebrafish olfactory epithelium. FEBS J 2024; 291:2098-2133. [PMID: 38088047 DOI: 10.1111/febs.17033] [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: 11/06/2023] [Revised: 11/15/2023] [Accepted: 12/11/2023] [Indexed: 12/21/2023]
Abstract
Maintenance and regeneration of the zebrafish olfactory epithelium (OE) are supported by two distinct progenitor cell populations that occupy spatially discrete stem cell niches and respond to different tissue conditions. Globose basal cells (GBCs) reside at the inner and peripheral margins of the sensory OE and are constitutively active to replace sporadically dying olfactory sensory neurons (OSNs). In contrast, horizontal basal cells (HBCs) are uniformly distributed across the sensory tissue and are selectively activated by acute injury conditions. Here we show that expression of the heparin-binding epidermal growth factor-like growth factor (HB-EGF) is strongly and transiently upregulated in response to OE injury and signals through the EGF receptor (EGFR), which is expressed by HBCs. Exogenous stimulation of the OE with recombinant HB-EGF promotes HBC expansion and OSN neurogenesis in a pattern that resembles the tissue response to injury. In contrast, pharmacological inhibition of HB-EGF membrane shedding, HB-EGF availability, and EGFR signaling strongly attenuate or delay injury-induced HBC activity and OSN restoration without affecting maintenance neurogenesis by GBCs. Thus, HB-EGF/EGFR signaling appears to be a critical component of the signaling network that controls HBC activity and, consequently, repair neurogenesis in the zebrafish OE.
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Affiliation(s)
- Siran Sireci
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Yigit Kocagöz
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Aysu Sevval Alkiraz
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Kardelen Güler
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Zeynep Dokuzluoglu
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Ecem Balcioglu
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Sinem Meydanli
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | - Mehmet Can Demirler
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
| | | | - Stefan Herbert Fuss
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogaziçi University, Istanbul, Türkiye
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14
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Yi SY, Wei MZ, Zhao L. Targeted immunotherapy to cancer stem cells: A novel strategy of anticancer immunotherapy. Crit Rev Oncol Hematol 2024; 196:104313. [PMID: 38428702 DOI: 10.1016/j.critrevonc.2024.104313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 02/04/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024] Open
Abstract
Cancer is a major disease that endangers human health. Cancer drug resistance and relapse are the two main causes contributing to cancer treatment failure. Cancer stem cells (CSCs) are a small fraction of tumor cells that are responsible for tumorigenesis, metastasis, relapse, and resistance to conventional anticancer therapies. Therefore, CSCs are considered to be the root of cancer recurrence, metastasis, and drug resistance. Novel anticancer strategies need to face this new challenge and explore their efficacy against CSCs. Recently, immunotherapy has made rapid advances in cancer treatment, and its potential against CSCs is also an interesting area of research. Meanwhile, immunotherapy strategies are novel therapeutic modalities with promising results in targeting CSCs. In this review, we summarize the targeting of CSCs by various immunotherapy strategies such as monoclonal antibodies(mAb), tumor vaccines, immune checkpoint inhibitors, and chimeric antigen receptor-T cells(CAR-T) in pre-clinical and clinical studies. This review provides new insights into the application of these immunotherapeutic approaches to potential anti-tumor therapies in the future.
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Affiliation(s)
- Shan-Yong Yi
- Department of Oncology of the Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zheng Zhou, Henan Province 450007, China.
| | - Mei-Zhuo Wei
- Department of Oncology of the Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zheng Zhou, Henan Province 450007, China
| | - Ling Zhao
- Department of Oncology of the Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zheng Zhou, Henan Province 450007, China.
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15
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Menbari Oskouie I, Zareian Baghdadabad L, Mashhadi R, Zahmatkesh P, Mirzaei A, Khajavi A, Noori M, Mesbah G, Aghamir SMK. Evaluation of the Effects of Opium on the Expression of SOX2 and OCT4 in Wistar Rat Bladder. Bladder Cancer 2024; 10:47-59. [PMID: 38993529 PMCID: PMC11181810 DOI: 10.3233/blc-230076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/26/2023] [Indexed: 07/13/2024]
Abstract
BACKGROUND Bladder cancer is a malignancy greatly affected by behavioral habits. The aim of this study was to examine the effect of opium on changes in the expression of OCT4 and SOX2 in the bladder tissue of rats. METHOD Thirty six rats were divided into six groups: 24 rats in the addicted group received morphine and opium for 4 months with 12 rats in the control group. Blood testing was done for the evaluation of CBC, MDA, and TAC. The bladder tissue was removed and checked by histopathological examination. All total RNA was extracted, then cDNAs were synthesized and the OCT4 and SOX2 gene expressions were evaluated by Real-time PCR. RESULTS The OCT4 mRNA expression level in the opium group of rats was significantly increased compared to the control group (13.5 and 6.8 fold in males and females respectively). Also, in the morphine group, similar augmentation was detected (3.8 and 6.7 fold in males and females respectively). The SOX2 mRNA over-expression level was seen in the morphine group of both genders as compared to the control group (3.7 and 4.2 fold in male and female respectively) but in the opium group, enhancement of mRNA level was seen only in males (6.6 fold). Opium increases both OCT4 and SOX2 expression more than morphine in male rats, but in female rats, SOX2 is increased more by morphine. CONCLUSION Over expression of OCT4 and SOX2 was observed in rats treated with opium and morphine. Increased OCT4 and SOX2 expression was seen in opium-treated male rats, but in female rats, SOX2 was increased more by morphine.
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Affiliation(s)
| | | | - Rahil Mashhadi
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Zahmatkesh
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Mirzaei
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Khajavi
- Student Research Committee, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Noori
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Mesbah
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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16
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Chen J, Li C, Sheng Y, Zhang J, Pang L, Dong Z, Wu Z, Lu Y, Liu Z, Zhang Q, Guan X, Chen X, Huang J. Communication between the stem cell niche and an adjacent differentiation niche through miRNA and EGFR signaling orchestrates exit from the stem cell state in the Drosophila ovary. PLoS Biol 2024; 22:e3002515. [PMID: 38512963 PMCID: PMC10986965 DOI: 10.1371/journal.pbio.3002515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 04/02/2024] [Accepted: 01/22/2024] [Indexed: 03/23/2024] Open
Abstract
The signaling environment, or niche, often governs the initial difference in behavior of an adult stem cell and a derivative that initiates a path towards differentiation. The transition between an instructive stem cell niche and differentiation niche must generally have single-cell resolution, suggesting that multiple mechanisms might be necessary to sharpen the transition. Here, we examined the Drosophila ovary and found that Cap cells, which are key constituents of the germline stem cell (GSC) niche, express a conserved microRNA (miR-124). Surprisingly, loss of miR-124 activity in Cap cells leads to a defect in differentiation of GSC derivatives. We present evidence that the direct functional target of miR-124 in Cap cells is the epidermal growth factor receptor (EGFR) and that failure to limit EGFR expression leads to the ectopic expression of a key anti-differentiation BMP signal in neighboring somatic escort cells (ECs), which constitute a differentiation niche. We further found that Notch signaling connects EFGR activity in Cap cells to BMP expression in ECs. We deduce that the stem cell niche communicates with the differentiation niche through a mechanism that begins with the selective expression of a specific microRNA and culminates in the suppression of the major anti-differentiation signal in neighboring cells, with the functionally important overall role of sharpening the spatial distinction between self-renewal and differentiation environments.
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Affiliation(s)
- Jiani Chen
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Chaosqun Li
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Yifeng Sheng
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Junwei Zhang
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Lan Pang
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Zhi Dong
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Zhiwei Wu
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Yueqi Lu
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Zhiguo Liu
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Qichao Zhang
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Xueying Guan
- Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
- Hainan Institute of Zhejiang University, Yazhou Bay Science and Technology City, Sanya, China
| | - Xuexin Chen
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
- Hainan Institute of Zhejiang University, Yazhou Bay Science and Technology City, Sanya, China
| | - Jianhua Huang
- Institute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, Zhejiang University, Hangzhou, China
- Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
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17
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Vidaurre V, Song A, Li T, Ku WL, Zhao K, Qian J, Chen X. The Drosophila histone methyl-transferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.14.580277. [PMID: 38405894 PMCID: PMC10888844 DOI: 10.1101/2024.02.14.580277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Many cell types come from tissue-specific adult stem cells that maintain the balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase, Set1, regulates early-stage male germ cell proliferation and differentiation in Drosophila. Early-stage germline-specific knockdown of set1 results in a temporally progressed defects, arising as germ cell loss and developing to overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage in a non-cell-autonomous manner. Additionally, wild-type Set1, but not the catalytically inactive Set1, could rescue the set1 knockdown phenotypes, highlighting the functional importance of the methyl-transferase activity of the Set1 enzyme. Further, RNA-seq experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene stat92E and the BMP pathway gene mad, that are upregulated upon set1 knockdown. Genetic interaction assays support the functional relationships between set1 and JAK-STAT or BMP pathways, as mutations of both the stat92E and mad genes suppress the set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The germ cell loss followed by over-proliferation phenotypes when inhibiting a histone methyl-transferase raise concerns about using their inhibitors in cancer therapy.
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Affiliation(s)
- Velinda Vidaurre
- Department of Biology, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Annabelle Song
- Department of Biology, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Taibo Li
- Department of Biology, The Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Wai Lim Ku
- Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, United States of America
| | - Keji Zhao
- Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, United States of America
| | - Jiang Qian
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Xin Chen
- Howard Hughes Medical Institute, Baltimore, Maryland, United States of America
- Department of Biology, The Johns Hopkins University, Baltimore, Maryland, United States of America
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18
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Liang S, Hess J. Tumor Neurobiology in the Pathogenesis and Therapy of Head and Neck Cancer. Cells 2024; 13:256. [PMID: 38334648 PMCID: PMC10854684 DOI: 10.3390/cells13030256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/20/2024] [Accepted: 01/26/2024] [Indexed: 02/10/2024] Open
Abstract
The neurobiology of tumors has attracted considerable interest from clinicians and scientists and has become a multidisciplinary area of research. Neural components not only interact with tumor cells but also influence other elements within the TME, such as immune cells and vascular components, forming a polygonal relationship to synergistically facilitate tumor growth and progression. This review comprehensively summarizes the current state of the knowledge on nerve-tumor crosstalk in head and neck cancer and discusses the potential underlying mechanisms. Several mechanisms facilitating nerve-tumor crosstalk are covered, such as perineural invasion, axonogenesis, neurogenesis, neural reprogramming, and transdifferentiation, and the reciprocal interactions between the nervous and immune systems in the TME are also discussed in this review. Further understanding of the nerve-tumor crosstalk in the TME of head and neck cancer may provide new nerve-targeted treatment options and help improve clinical outcomes for patients.
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Affiliation(s)
- Siyuan Liang
- Department of Otorhinolaryngology, Head and Neck Tumors, Heidelberg University Hospital, 69120 Heidelberg, Germany;
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Tumors, Heidelberg University Hospital, 69120 Heidelberg, Germany;
- Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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19
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Eslami M, Memarsadeghi O, Davarpanah A, Arti A, Nayernia K, Behnam B. Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines 2024; 12:183. [PMID: 38255288 PMCID: PMC10812960 DOI: 10.3390/biomedicines12010183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/17/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.
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Affiliation(s)
- Maryam Eslami
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Omid Memarsadeghi
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Ali Davarpanah
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Afshin Arti
- Department of Biomedical Engineering, Central Tehran Branch, Islamic Azad University, Tehran 1469669191, Iran;
| | - Karim Nayernia
- International Center for Personalized Medicine (P7Medicine), 40235 Dusseldorf, Germany
| | - Babak Behnam
- Department of Regulatory Affairs, Amarex Clinical Research, NSF International, Germantown, MD 20874, USA
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20
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Das S, Dey MK, Devireddy R, Gartia MR. Biomarkers in Cancer Detection, Diagnosis, and Prognosis. SENSORS (BASEL, SWITZERLAND) 2023; 24:37. [PMID: 38202898 PMCID: PMC10780704 DOI: 10.3390/s24010037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/27/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024]
Abstract
Biomarkers are vital in healthcare as they provide valuable insights into disease diagnosis, prognosis, treatment response, and personalized medicine. They serve as objective indicators, enabling early detection and intervention, leading to improved patient outcomes and reduced costs. Biomarkers also guide treatment decisions by predicting disease outcomes and facilitating individualized treatment plans. They play a role in monitoring disease progression, adjusting treatments, and detecting early signs of recurrence. Furthermore, biomarkers enhance drug development and clinical trials by identifying suitable patients and accelerating the approval process. In this review paper, we described a variety of biomarkers applicable for cancer detection and diagnosis, such as imaging-based diagnosis (CT, SPECT, MRI, and PET), blood-based biomarkers (proteins, genes, mRNA, and peptides), cell imaging-based diagnosis (needle biopsy and CTC), tissue imaging-based diagnosis (IHC), and genetic-based biomarkers (RNAseq, scRNAseq, and spatial transcriptomics).
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Affiliation(s)
| | | | | | - Manas Ranjan Gartia
- Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA 70803, USA; (S.D.); (M.K.D.); (R.D.)
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21
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Montes-Olivas S, Legge D, Lund A, Fletcher AG, Williams AC, Marucci L, Homer M. In-silico and in-vitro morphometric analysis of intestinal organoids. PLoS Comput Biol 2023; 19:e1011386. [PMID: 37578984 PMCID: PMC10473498 DOI: 10.1371/journal.pcbi.1011386] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 09/01/2023] [Accepted: 07/25/2023] [Indexed: 08/16/2023] Open
Abstract
Organoids offer a powerful model to study cellular self-organisation, the growth of specific tissue morphologies in-vitro, and to assess potential medical therapies. However, the intrinsic mechanisms of these systems are not entirely understood yet, which can result in variability of organoids due to differences in culture conditions and basement membrane extracts used. Improving the standardisation of organoid cultures is essential for their implementation in clinical protocols. Developing tools to assess and predict the behaviour of these systems may produce a more robust and standardised biological model to perform accurate clinical studies. Here, we developed an algorithm to automate crypt-like structure counting on intestinal organoids in both in-vitro and in-silico images. In addition, we modified an existing two-dimensional agent-based mathematical model of intestinal organoids to better describe the system physiology, and evaluated its ability to replicate budding structures compared to new experimental data we generated. The crypt-counting algorithm proved useful in approximating the average number of budding structures found in our in-vitro intestinal organoid culture images on days 3 and 7 after seeding. Our changes to the in-silico model maintain the potential to produce simulations that replicate the number of budding structures found on days 5 and 7 of in-vitro data. The present study aims to aid in quantifying key morphological structures and provide a method to compare both in-vitro and in-silico experiments. Our results could be extended later to 3D in-silico models.
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Affiliation(s)
- Sandra Montes-Olivas
- Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom
| | - Danny Legge
- Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
| | - Abbie Lund
- Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom
| | - Alexander G. Fletcher
- School of Mathematics and Statistics, University of Sheffield, Sheffield, United Kingdom
- Bateson Centre, University of Sheffield, Sheffield, United Kingdom
| | - Ann C. Williams
- Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
| | - Lucia Marucci
- Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
- BrisSynBio, Bristol, United Kingdom
| | - Martin Homer
- Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom
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22
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Mitra Ghosh T, Mazumder S, Davis J, Yadav J, Akinpelu A, Alnaim A, Kumar H, Waliagha R, Church Bird AE, Rais-Bahrami S, Bird RC, Mistriotis P, Mishra A, Yates CC, Mitra AK, Arnold RD. Metronomic Administration of Topotecan Alone and in Combination with Docetaxel Inhibits Epithelial-mesenchymal Transition in Aggressive Variant Prostate Cancers. CANCER RESEARCH COMMUNICATIONS 2023; 3:1286-1311. [PMID: 37476073 PMCID: PMC10355222 DOI: 10.1158/2767-9764.crc-22-0427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/29/2023] [Accepted: 06/21/2023] [Indexed: 07/22/2023]
Abstract
Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiotherapy remain the primary treatment for patients with early-stage prostate cancer (castration-sensitive prostate cancer). Following ADT, many patients ultimately develop metastatic castration-resistant prostate cancer (mCRPC). Standard chemotherapy options for CRPC are docetaxel (DTX) and cabazitaxel, which increase median survival, although the development of resistance is common. Cancer stem-like cells possess mesenchymal phenotypes [epithelial-to-mesenchymal transition (EMT)] and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits prostate cancer growth by interfering with key cancer pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis [(RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq)], and we observed greater expression of several EMT markers, including Vimentin, hyaluronan synthase-3, S100 calcium binding protein A6, TGFB1, CD44, CD55, and CD109 in European American and African American aggressive variant prostate cancer (AVPC) subtypes-mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene FSCN1 was also expressed highly in single-cell subclonal populations in mCRPC. Furthermore, metronomic-topotecan single agent and combinations with DTX downregulated these EMT markers as well as CD44+ and CD44+/CD133+ "stem-like" cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single agent or in combination with DTX was potentially effective against invasive prostate cancer spread. Our RNA-seq and scRNA-seq analysis were supported by in silico and in vitro studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways. Significance The utilization of metronomic-like dosing regimens of topotecan alone and in combination with DTX resulted in the suppression of makers associated with EMT and stem-like cell populations in AVPC models. The identification of molecular signatures and their potential to serve as novel biomarkers for monitoring treatment efficacy and disease progression response to treatment efficacy and disease progression were achieved using bulk RNA-seq and single-cell-omics methodologies.
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Affiliation(s)
- Taraswi Mitra Ghosh
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
- Division of Urology, Department of Surgery, Mass General Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Suman Mazumder
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
- Center for Pharmacogenomics and Single-Cell Omics (AUPharmGx), Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Joshua Davis
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Jyoti Yadav
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Ayuba Akinpelu
- Department of Chemical Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, Alabama
| | - Ahmed Alnaim
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Harish Kumar
- Department of Biology and Canter for Cancer Research, Tuskegee University, Tuskegee, Alabama
| | - Razan Waliagha
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Allison E. Church Bird
- Flow Cytometry and High-Speed Cell Sorting Laboratory, Auburn University, Auburn, Alabama
| | - Soroush Rais-Bahrami
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
- Department of Urology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
- Department of Radiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
- Department of Pathology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
| | - R. Curtis Bird
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Panagiotis Mistriotis
- Department of Chemical Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, Alabama
| | - Amarjit Mishra
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
| | - Clayton C. Yates
- Department of Biology and Canter for Cancer Research, Tuskegee University, Tuskegee, Alabama
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
- Department of Pathology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Amit K. Mitra
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
- Center for Pharmacogenomics and Single-Cell Omics (AUPharmGx), Harrison College of Pharmacy, Auburn University, Auburn, Alabama
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
| | - Robert D. Arnold
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, Alabama
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama
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23
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Gupta R, Kadhim MM, Turki Jalil A, Obayes AM, Aminov Z, Alsaikhan F, Ramírez-Coronel AA, Ramaiah P, Tayyib NA, Luo X. Multifaceted role of NF-κB in hepatocellular carcinoma therapy: Molecular landscape, therapeutic compounds and nanomaterial approaches. ENVIRONMENTAL RESEARCH 2023; 228:115767. [PMID: 36966991 DOI: 10.1016/j.envres.2023.115767] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 05/16/2023]
Abstract
The predominant kind of liver cancer is hepatocellular carcinoma (HCC) that its treatment have been troublesome difficulties for physicians due to aggressive behavior of tumor cells in proliferation and metastasis. Moreover, stemness of HCC cells can result in tumor recurrence and angiogenesis occurs. Another problem is development of resistance to chemotherapy and radiotherapy in HCC cells. Genomic mutations participate in malignant behavior of HCC and nuclear factor-kappaB (NF-κB) has been one of the oncogenic factors in different human cancers that after nuclear translocation, it binds to promoter of genes in regulating their expression. Overexpression of NF-κB has been well-documented in increasing proliferation and invasion of tumor cells and notably, when its expression enhances, it induces chemoresistance and radio-resistance. Highlighting function of NF-κB in HCC can shed some light on the pathways regulating progression of tumor cells. The first aspect is proliferation acceleration and apoptosis inhibition in HCC cells mediated by enhancement in expression level of NF-κB. Moreover, NF-κB is able to enhance invasion of HCC cells via upregulation of MMPs and EMT, and it triggers angiogenesis as another step for increasing spread of tumor cells in tissues and organs. When NF-κB expression enhances, it stimulates chemoresistance and radio-resistance in HCC cells and by increasing stemness and population of cancer-stem cells, it can provide the way for recurrence of tumor. Overexpression of NF-κB mediates therapy resistance in HCC cells and it can be regulated by non-coding RNAs in HCC. Moreover, inhibition of NF-κB by anti-cancer and epigenetic drugs suppresses HCC tumorigenesis. More importantly, nanoparticles are considered for suppressing NF-κB axis in cancer and their prospectives and results can also be utilized for treatment of HCC. Nanomaterials are promising factors in treatment of HCC and by delivery of genes and drugs, they suppress HCC progression. Furthermore, nanomaterials provide phototherapy in HCC ablation.
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Affiliation(s)
- Reena Gupta
- Institute of Pharmaceutical Research, GLA University, District-Mathura, U. P., India
| | - Mustafa M Kadhim
- Department of Dentistry, Kut University College, Kut, Wasit, 52001, Iraq; Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad, 10022, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq.
| | | | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan; Department of Scientific Affairs, Tashkent State Dental Institute, 103 Makhtumkuli Str., Tashkent, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Ecuador; Epidemiology and Biostatistics Research Group, CES University, Colombia; Educational Statistics Research Group (GIEE), National University of Education, Ecuador
| | | | - Nahla A Tayyib
- Faculty of Nursing, Umm al- Qura University, Makkah, Saudi Arabia
| | - Xuanming Luo
- Department of General Surgery, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, 200031, China.
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24
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Wilczyński JR, Wilczyński M, Paradowska E. "DEPHENCE" system-a novel regimen of therapy that is urgently needed in the high-grade serous ovarian cancer-a focus on anti-cancer stem cell and anti-tumor microenvironment targeted therapies. Front Oncol 2023; 13:1201497. [PMID: 37448521 PMCID: PMC10338102 DOI: 10.3389/fonc.2023.1201497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Ovarian cancer, especially high-grade serous type, is the most lethal gynecological malignancy. The lack of screening programs and the scarcity of symptomatology result in the late diagnosis in about 75% of affected women. Despite very demanding and aggressive surgical treatment, multiple-line chemotherapy regimens and both approved and clinically tested targeted therapies, the overall survival of patients is still unsatisfactory and disappointing. Research studies have recently brought some more understanding of the molecular diversity of the ovarian cancer, its unique intraperitoneal biology, the role of cancer stem cells, and the complexity of tumor microenvironment. There is a growing body of evidence that individualization of the treatment adjusted to the molecular and biochemical signature of the tumor as well as to the medical status of the patient should replace or supplement the foregoing therapy. In this review, we have proposed the principles of the novel regimen of the therapy that we called the "DEPHENCE" system, and we have extensively discussed the results of the studies focused on the ovarian cancer stem cells, other components of cancer metastatic niche, and, finally, clinical trials targeting these two environments. Through this, we have tried to present the evolving landscape of treatment options and put flesh on the experimental approach to attack the high-grade serous ovarian cancer multidirectionally, corresponding to the "DEPHENCE" system postulates.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, Lodz, Poland
| | - Miłosz Wilczyński
- Department of Gynecological, Endoscopic and Oncological Surgery, Polish Mother's Health Center-Research Institute, Lodz, Poland
- Department of Surgical and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, Poland
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25
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Otsuka K, Iwasaki T. Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells. Int J Radiat Biol 2023; 99:1503-1521. [PMID: 36971595 DOI: 10.1080/09553002.2023.2194398] [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: 05/05/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
PURPOSE Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells. METHODS We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation. RESULTS Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition. CONCLUSIONS We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.
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Affiliation(s)
- Kensuke Otsuka
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
| | - Toshiyasu Iwasaki
- Strategy and Planning Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
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26
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Zhou T, Zhang LY, He JZ, Miao ZM, Li YY, Zhang YM, Liu ZW, Zhang SZ, Chen Y, Zhou GC, Liu YQ. Review: Mechanisms and perspective treatment of radioresistance in non-small cell lung cancer. Front Immunol 2023; 14:1133899. [PMID: 36865554 PMCID: PMC9971010 DOI: 10.3389/fimmu.2023.1133899] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 01/31/2023] [Indexed: 02/16/2023] Open
Abstract
Radiotherapy is the major treatment of non-small cell lung cancer (NSCLC). The radioresistance and toxicity are the main obstacles that leading to therapeutic failure and poor prognosis. Oncogenic mutation, cancer stem cells (CSCs), tumor hypoxia, DNA damage repair, epithelial-mesenchymal transition (EMT), and tumor microenvironment (TME) may dominate the occurrence of radioresistance at different stages of radiotherapy. Chemotherapy drugs, targeted drugs, and immune checkpoint inhibitors are combined with radiotherapy to treat NSCLC to improve the efficacy. This article reviews the potential mechanism of radioresistance in NSCLC, and discusses the current drug research to overcome radioresistance and the advantages of Traditional Chinese medicine (TCM) in improving the efficacy and reducing the toxicity of radiotherapy.
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Affiliation(s)
- Ting Zhou
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,Experimental & Training Teaching Centers, Gansu University of Chinese Medicine, Lanzhou, China
| | - Li-Ying Zhang
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jian-Zheng He
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Zhi-Ming Miao
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yang-Yang Li
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yi-Ming Zhang
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Zhi-Wei Liu
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Shang-Zu Zhang
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yan Chen
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Gu-Cheng Zhou
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yong-Qi Liu
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, China,College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China,Key Laboratory of Dunhuang Medicine and Transformation at Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou, China,*Correspondence: Yong-Qi Liu,
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27
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Vienot A, Monnien F, Truntzer C, Mougey V, Bouard A, Pallandre JR, Molimard C, Loyon R, Asgarov K, Averous G, Ghiringhelli F, Bibeau F, Peixoto P, Borg C. SALL4-related gene signature defines a specific stromal subset of pancreatic ductal adenocarcinoma with poor prognostic features. Mol Oncol 2023. [PMID: 36587397 DOI: 10.1002/1878-0261.13370] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 11/20/2022] [Accepted: 12/30/2022] [Indexed: 01/02/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is marked by molecular heterogeneity and poor prognosis. Among the stemness-related transcription factors, Spalt-like Transcription Factor 4 (SALL4) is correlated with unfavorable outcomes; however, its roles in PDAC remain unclear. SALL4high expression defines a PDAC subpopulation characterized by a shortened patient survival. Although SALL4 expression was mostly evaluated in tumor cells, our findings identify this embryonic transcription factor as a new biomarker in PDAC-derived stroma. Gene expression analysis reveals that the SALL4high PDAC subset is enriched in cancer stem cell properties and stromal enrichment pathways; notably, an interaction with cancer-associated fibroblasts (CAF) activated by TGF-β. A particular oncogenic network was unraveled where Netrin-1 and TGF-β1 collaborate to induce SALL4 expression in CAF and drive their cancer-stemness-promoting functions. A 7-gene stromal signature related to SALL4high PDAC samples was highlighted and validated by immunochemistry for prognosis and clinical application. This SALL4-related stroma discriminated pancreatic preinvasive from invasive lesions and was enriched in short-term survivors. Our results show that SALL4 transcriptional activity controls a molecular network defined by a specific stromal signature that characterizes PDAC invasiveness and worse clinical outcomes.
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Affiliation(s)
- Angélique Vienot
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, France.,Clinical Investigational Center, CIC-1431, Besançon, France.,ITAC Platform, University of Bourgogne Franche-Comté, Besançon, France
| | - Franck Monnien
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,Department of Pathology, University Hospital of Besançon, France
| | - Caroline Truntzer
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Center-Unicancer, Dijon, France.,UMR INSERM 1231, Dijon, France
| | - Virginie Mougey
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,ITAC Platform, University of Bourgogne Franche-Comté, Besançon, France
| | - Adeline Bouard
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,ITAC Platform, University of Bourgogne Franche-Comté, Besançon, France
| | - Jean-René Pallandre
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
| | - Chloé Molimard
- Department of Pathology, University Hospital of Besançon, France
| | - Romain Loyon
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
| | - Kamal Asgarov
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,ITAC Platform, University of Bourgogne Franche-Comté, Besançon, France
| | - Gerlinde Averous
- Department of Pathology, University Hospital of Strasbourg, France
| | - François Ghiringhelli
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Center-Unicancer, Dijon, France.,UMR INSERM 1231, Dijon, France
| | - Frédéric Bibeau
- Department of Pathology, University Hospital of Besançon, France
| | - Paul Peixoto
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,EPIgenetics and GENe EXPression Technical Platform (EPIGENExp), University of Bourgogne Franche-Comté, Besançon, France
| | - Christophe Borg
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, France.,Clinical Investigational Center, CIC-1431, Besançon, France.,ITAC Platform, University of Bourgogne Franche-Comté, Besançon, France
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28
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Ray S. Tumorsphere Formation Assay: A Cancer Stem-Like Cell Characterization in Pediatric Brain Cancer Medulloblastoma. Methods Mol Biol 2023; 2701:253-259. [PMID: 37574488 DOI: 10.1007/978-1-0716-3373-1_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Cancer is a heterogeneous disease, comprising of a mixture of different cell populations. Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are a subpopulation of multipotent cells within the cancer that has self-renewing capability, tumor-initiating ability, multi-differentiation potential, and an inherent capacity for drug and chemoresistance. Sphere-formation assay is commonly used for enrichment and analysis of CSC properties in vitro and is typically used as a metric for testing the viability of tumor cells to anticancer agents. This model is based on the ability of CSCs to grow under ultralow-attachment conditions in serum-free medium supplemented with growth factors. In contrast to the adherent 2D culture of cancer cells, the 3D culture of tumorsphere assay exploits inherent biologic features of CSCs such as anoikis resistance and self-renewal. We describe here the detailed methodology for the generation and propagation of spheres generated from pediatric brain tumor medulloblastoma (MB) cells. As signal transducer and activator of transcription (STAT3) is known to play an important role in maintaining cancer stem cell properties, we accessed the effect of depleting or inhibiting STAT3 on MB-sphere sizes, numbers, and integrity. This may serve as a promising platform for screening potential anti-CSC agents and small-molecule inhibitors.
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Affiliation(s)
- Sutapa Ray
- Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE, USA.
- Fred and Pamela Buffett Cancer Center, Omaha, NE, USA.
- Child Health Research Institute, Omaha, NE, USA.
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29
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Mukherjee S, Calvi BR, Hundley HA, Sokol NS. MicroRNA mediated regulation of the onset of enteroblast differentiation in the Drosophila adult intestine. Cell Rep 2022; 41:111495. [DOI: 10.1016/j.celrep.2022.111495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 08/17/2022] [Accepted: 09/21/2022] [Indexed: 11/03/2022] Open
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30
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Zhou S, Li M, Ostrow D, Ruble D, Mascarenhas L, Pawel B, Buckley JD, Triche TJ. Potential methylation-regulated genes and pathways in hepatocellular neoplasm, not otherwise specified. Front Oncol 2022; 12:952325. [PMID: 36212481 PMCID: PMC9532972 DOI: 10.3389/fonc.2022.952325] [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: 05/25/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Background and Aims The molecular basis of hepatocellular neoplasm, not otherwise specified (HCN-NOS) is unknown. We aimed to identify gene expression patterns, potential methylation-regulated genes and pathways that characterize the tumor, and its possible relationship to hepatoblastoma and hepatocellular carcinoma (HCC). Approach & Results Parallel genome-wide profiling of gene expression (RNAseq) and DNA methylation (EPIC850) was performed on 4 pairs of pre-treatment HCN-NOS tumors and adjacent non-tumor controls. 2530 significantly differentially expressed genes (DEGs) were identified between tumors and controls. Many of these DEGs were associated with hepatoblastoma and/or HCC. Analysis Match in Ingenuity Pathway Analysis determined that the gene expression profile of HCN-NOS was unique but significantly similar to that of both hepatoblastoma and HCC. A total of 27,195 CpG sites (CpGs) were significantly differentially methylated (DM) between tumors and controls, with a global hypomethylation pattern and predominant CpG island hypermethylation in promotor regions. Aberrant DNA methylation predominated in Developmental Process and Molecular Function Regulator pathways. Embryonic stem cell pathways were significantly enriched. In total, 1055 aberrantly methylated (at CpGs) and differentially expressed genes were identified, including 25 upstream regulators and sixty-one potential CpG island methylation-regulated genes. Eight methylation-regulated genes (TCF3, MYBL2, SRC, HMGA2, PPARGC1A, SLC22A1, COL2A1 and MYCN) had highly consistent gene expression patterns and prognostic value in patients with HCC, based on comparison to publicly available datasets. Conclusions HCN-NOS has a unique, stem-cell like gene expression and DNA methylation profile related to both hepatoblastoma and HCC but distinct therefrom. Further, 8 methylation-regulated genes associated with prognosis in HCC were identified.
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Affiliation(s)
- Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Shengmei Zhou,
| | - Meng Li
- USC Libraries Bioinformatics Services, University of Southern California, Los Angeles, CA, United States
| | - Dejerianne Ostrow
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - David Ruble
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Leo Mascarenhas
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Cancer and Blood Disease Institute, Division of Hematology/Oncology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Bruce Pawel
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jonathan David Buckley
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Timothy J. Triche
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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31
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Park S, Park JM, Park M, Ko D, Kim S, Seo J, Nam KD, Jung E, Farrand L, Kim YJ, Kim JY, Seo JH. β-Escin overcomes trastuzumab resistance in HER2-positive breast cancer by targeting cancer stem-like features. Cancer Cell Int 2022; 22:289. [PMID: 36127671 PMCID: PMC9490928 DOI: 10.1186/s12935-022-02713-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/09/2022] [Indexed: 11/15/2022] Open
Abstract
Background The emergence of de novo or intrinsic trastuzumab resistance is exceedingly high in breast cancer that is HER2 positive and correlates with an abundant cancer stem cell (CSC)-like population. We sought to examine the capacity of β-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells. Methods The effect of β-escin on trastuzumab-resistant and -sensitive cell lines in vitro was evaluated for apoptosis, expression of HER2 family members, and impact on CSC-like properties. An in vivo model of trastuzumab-resistant JIMT-1 was used to examine the efficacy and toxicity of β-escin. Results β-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. Attenuation of CSC-related features by β-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. β-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, β-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals. Conclusions Taken together, our findings highlight β-escin as a promising candidate for the treatment of trastuzumab-resistant HER2-positive breast cancers. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02713-9.
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Affiliation(s)
- Soeun Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Jung Min Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Minsu Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Dongmi Ko
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Seongjae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Juyeon Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Kee Dal Nam
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Eunsun Jung
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea
| | - Lee Farrand
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Yoon-Jae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. .,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. .,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea.
| | - Ji Young Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. .,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea.
| | - Jae Hong Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. .,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. .,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 97 Gurodong-gil, Guro-gu, Seoul, 08308, Republic of Korea.
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Mahmoud R, Ordóñez-Morán P, Allegrucci C. Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness. Cancers (Basel) 2022; 14:cancers14174280. [PMID: 36077812 PMCID: PMC9454775 DOI: 10.3390/cancers14174280] [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: 07/06/2022] [Revised: 08/12/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which are not specific and do not target resistant cells. Therefore, one of the major clinical challenges is to find compounds that target the drug-resistant cell populations which are responsible for reforming secondary tumours. The molecular profiling of the different TNBC subtypes holds a promise for better defining these resistant cells specific to each tumour. To this end, a better understanding of TNBC heterogeneity and cancer stemness is required, and extensive genomic analysis can help to understand the disease complexity and distinguish new molecular drivers that can be targeted in the clinics. The use of persister cancer cell-targeting therapies combined with other therapies may provide a big advance to improve TNBC patients' survival.
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Affiliation(s)
- Rinad Mahmoud
- Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
| | - Paloma Ordóñez-Morán
- Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
- Correspondence: (P.O.-M.); (C.A.)
| | - Cinzia Allegrucci
- Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- Nottingham Breast Cancer Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- SVMS, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK
- Correspondence: (P.O.-M.); (C.A.)
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33
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Zhao J, Li M, Xu J, Cheng W. The modulation of ion channels in cancer chemo-resistance. Front Oncol 2022; 12:945896. [PMID: 36033489 PMCID: PMC9399684 DOI: 10.3389/fonc.2022.945896] [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: 05/17/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022] Open
Abstract
Ion channels modulate the flow of ions into and out of a cell or intracellular organelle, leading to generation of electrical or chemical signals and regulating ion homeostasis. The abundance of ion channels in the plasma and intracellular membranes are subject to physiological and pathological regulations. Abnormal and dysregulated expressions of many ion channels are found to be linked to cancer and cancer chemo-resistance. Here, we will summarize ion channels distribution in multiple tumors. And the involvement of ion channels in cancer chemo-resistance will be highlighted.
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34
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Masola V, Franchi M, Zaza G, Atsina FM, Gambaro G, Onisto M. Heparanase regulates EMT and cancer stem cell properties in prostate tumors. Front Oncol 2022; 12:918419. [PMID: 35965510 PMCID: PMC9363836 DOI: 10.3389/fonc.2022.918419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Prostate cancer displays a certain phenotypic plasticity that allows for the transition of cells from the epithelial to the mesenchymal state. This process, known as epithelial–mesenchymal transition (EMT), is one of the factors that give the tumor cells greater invasive and migratory capacity with subsequent formation of metastases. In addition, many cancers, including prostate cancer, are derived from a cell population that shows the properties of stem cells. These cells, called cancer stem cells (CSCs) or tumor-initiating cells, not only initiate the tumor process and growth but are also able to mediate metastasis and drug resistance. However, the impact of EMT and CSCs in prostate cancer progression and patient survival is still far from fully understood. Heparanase (HPSE), the sole mammalian endoglycosidase capable of degrading heparan sulfate (HS), is also involved in prostate cancer progression. We had previously proved that HPSE regulates EMT in non-cancerous pathologies. Two prostate cancer cell lines (DU145 and PC3) were silenced and overexpressed for HPSE. Expression of EMT and stemness markers was evaluated. Results showed that the expression of several EMT markers are modified by HPSE expression in both the prostate cancer cell lines analyzed. In the same way, the stemness markers and features are also modulated by HPSE expression. Taken together, the present findings seem to prove a new mechanism of action of HPSE in sustaining prostate cancer growth and diffusion. As for other tumors, these results highlight the importance of HPSE as a potential pharmacological target in prostate cancer treatment.
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Affiliation(s)
- Valentina Masola
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- *Correspondence: Maurizio Onisto, ; Valentina Masola,
| | - Marco Franchi
- Department of Life Quality Sciences, University of Bologna, Rimini, Italy
| | - Gianluigi Zaza
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Giovanni Gambaro
- Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- *Correspondence: Maurizio Onisto, ; Valentina Masola,
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35
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Soni M, Saatci O, Gupta G, Patel Y, Keerthi Raja MR, Li J, Liu X, Xu P, Wang H, Fan D, Sahin O, Chen H. miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer. Int J Mol Sci 2022; 23:ijms23158086. [PMID: 35897675 PMCID: PMC9331933 DOI: 10.3390/ijms23158086] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023] Open
Abstract
Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.
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Affiliation(s)
- Mithil Soni
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Ozge Saatci
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Gourab Gupta
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Yogin Patel
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Manikanda Raja Keerthi Raja
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Jie Li
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29201, USA;
| | - Xinfeng Liu
- Department of Mathematics, University of South Carolina, Columbia, SC 29201, USA;
| | - Peisheng Xu
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Hongjun Wang
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA;
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA;
| | - Ozgur Sahin
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Hexin Chen
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
- Correspondence: ; Tel.: +1-803-777-2928; Fax: +1-803-777-4002
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36
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Regan JL, Schumacher D, Staudte S, Steffen A, Lesche R, Toedling J, Jourdan T, Haybaeck J, Golob-Schwarzl N, Mumberg D, Henderson D, Győrffy B, Regenbrecht CR, Keilholz U, Schäfer R, Lange M. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis. iScience 2022; 25:104498. [PMID: 35720265 PMCID: PMC9204726 DOI: 10.1016/j.isci.2022.104498] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/28/2022] [Accepted: 05/26/2022] [Indexed: 11/12/2022] Open
Abstract
Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPositive CSCs from colon cancer patient-derived organoids (PDOs) and xenografts (PDXs) showed CSCs to be enriched for neural development genes. Functional analyses of genes differentially expressed in CSCs from PDO and PDX models demonstrated the neural crest stem cell (NCSC) regulator EGR2 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator HOX genes and the neural stem cell and master cell fate regulator SOX2. These data support CSCs as the source of tumor neurogenesis and suggest that targeting EGR2 may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.
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Affiliation(s)
- Joseph L. Regan
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Dirk Schumacher
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Stephanie Staudte
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
- Department of Radiation Oncology and Radiotherapy, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Andreas Steffen
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Ralf Lesche
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Joern Toedling
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Thibaud Jourdan
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
| | - Nicole Golob-Schwarzl
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Department of Dermatology and Venereology, Medical University of Graz, 8036 Graz, Austria
| | - Dominik Mumberg
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - David Henderson
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Bayer AG, Business Development and Licensing and Open Innovation, Pharmaceuticals, 13342 Berlin, Germany
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary
- TTK Cancer Biomarker Research Group, Institute of Enzymology, 1117 Budapest, Hungary
| | - Christian R.A. Regenbrecht
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- CELLphenomics GmbH, 13125 Berlin, Germany
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Reinhold Schäfer
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Martin Lange
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
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Tatari N, Zhang X, Chafe SC, McKenna D, Lawson KA, Subapanditha M, Shaikh MV, Seyfrid M, Savage N, Venugopal C, Moffat J, Singh SK. Dual Antigen T Cell Engagers Targeting CA9 as an Effective Immunotherapeutic Modality for Targeting CA9 in Solid Tumors. Front Immunol 2022; 13:905768. [PMID: 35874663 PMCID: PMC9296860 DOI: 10.3389/fimmu.2022.905768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/31/2022] [Indexed: 12/04/2022] Open
Abstract
Glioblastomas (GBM), the most common malignant primary adult brain tumors, are uniformly lethal and are in need of improved therapeutic modalities. GBM contain extensive regions of hypoxia and are enriched in therapy resistant brain tumor-initiating cells (BTICs). Carbonic anhydrase 9 (CA9) is a hypoxia-induced cell surface enzyme that plays an important role in maintenance of stem cell survival and therapeutic resistance. Here we demonstrate that CA9 is highly expressed in patient-derived BTICs. CA9+ GBM BTICs showed increased self-renewal and proliferative capacity. To target CA9, we developed dual antigen T cell engagers (DATEs) that were exquisitely specific for CA9-positive patient-derived clear cell Renal Cell Carcinoma (ccRCC) and GBM cells. Combined treatment of either ccRCC or GBM cells with the CA9 DATE and T cells resulted in T cell activation, increased release of pro-inflammatory cytokines and enhanced cytotoxicity in a CA9-dependent manner. Treatment of ccRCC and GBM patient-derived xenografts markedly reduced tumor burden and extended survival. These data suggest that the CA9 DATE could provide a novel therapeutic strategy for patients with solid tumors expressing CA9 to overcome treatment resistance.
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Affiliation(s)
- Nazanin Tatari
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Xiaoyu Zhang
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Shawn C. Chafe
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Dillon McKenna
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Keith A. Lawson
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Minomi Subapanditha
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Muhammad Vaseem Shaikh
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Mathieu Seyfrid
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Neil Savage
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Chitra Venugopal
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Jason Moffat
- Donnelly Centre, University of Toronto, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Sheila K. Singh
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
- Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- *Correspondence: Sheila K. Singh,
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Sukocheva OA, Lukina E, Friedemann M, Menschikowski M, Hagelgans A, Aliev G. The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives. Semin Cancer Biol 2022; 82:35-59. [PMID: 33301860 DOI: 10.1016/j.semcancer.2020.12.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/22/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.
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Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia.
| | - Elena Lukina
- Discipline of Biology, College of Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia
| | - Markus Friedemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Federal State Budgetary Institution «Research Institute of Human Morphology», 3, Tsyurupy Str., Moscow, 117418, Russian Federation; GALLY International Research Institute, San Antonio, TX, 78229, USA.
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Rezayatmand H, Razmkhah M, Razeghian-Jahromi I. Drug resistance in cancer therapy: the Pandora's Box of cancer stem cells. Stem Cell Res Ther 2022; 13:181. [PMID: 35505363 PMCID: PMC9066908 DOI: 10.1186/s13287-022-02856-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/14/2022] [Indexed: 12/18/2022] Open
Abstract
Drug resistance is the main culprit of failure in cancer therapy that may lead to cancer relapse. This resistance mostly originates from rare, but impactful presence of cancer stem cells (CSCs). Ability to self-renewal and differentiation into heterogeneous cancer cells, and harboring morphologically and phenotypically distinct cells are prominent features of CSCs. Also, CSCs substantially contribute to metastatic dissemination. They possess several mechanisms that help them to survive even after exposure to chemotherapy drugs. Although chemotherapy is able to destroy the bulk of tumor cells, CSCs are left almost intact, and make tumor entity resistant to treatment. Eradication of a tumor mass needs complete removal of tumor cells as well as CSCs. Therefore, it is important to elucidate key features underlying drug resistance raised by CSCs in order to apply effective treatment strategies. However, the challenging point that threatens safety and specificity of chemotherapy is the common characteristics between CSCs and normal peers such as signaling pathways and markers. In the present study, we tried to present a comprehensive appraisal on CSCs, mechanisms of their drug resistance, and recent therapeutic methods targeting this type of noxious cells.
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Affiliation(s)
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Razeghian-Jahromi
- Cardiovascular Research Center, Shiraz University of Medical Sciences, 3rd Floor, Mohammad Rasoolallah Research Tower, Namazi Hospital, Shiraz, Iran.
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Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers. Int J Mol Sci 2022; 23:ijms23073596. [PMID: 35408953 PMCID: PMC8998882 DOI: 10.3390/ijms23073596] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/20/2022] [Accepted: 03/23/2022] [Indexed: 02/04/2023] Open
Abstract
Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been questioned by studies showing that single unselected melanoma cells are highly tumorigenic in xenotransplantation assays. Herein, we characterize cells expressing MIC markers (CD20, CD24, CD133, Sca-1, ABCB1, ABCB5, ALDHhigh) in the B16-F10 murine melanoma cell line. We use flow cytometric phenotyping, single-cell sorting followed by in vitro clonogenic assays, and syngeneic in vivo serial transplantation assays to demonstrate that the expression of MIC markers does not select CSC-like cells in this cell line. Previously, our group showed that heme-degrading enzyme heme oxygenase-1 (HO-1) can be upregulated in melanoma and increase its aggressiveness. Here, we show that HO-1 activity is important for non-adherent growth of melanoma and HO-1 overexpression enhances the vasculogenic mimicry potential, which can be considered protumorigenic activity. However, HO-1 overexpression decreases clone formation in vitro and serial tumor initiation in vivo. Thus, HO-1 plays a dual role in melanoma, improving the progression of growing tumors but reducing the risk of melanoma initiation.
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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