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1
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Alem D, García-Laviña CX, Garagorry F, Centurión D, Farias J, Pazos-Espinosa H, Cuitiño-Mendiberry MN, Villadóniga C, Castro-Sowinski S, Fló M, Carrión F, Iglesias B, Madauss K, Canclini L. Amyloids in bladder cancer hijack cancer-related proteins and are positive correlated to tumor stage. Sci Rep 2025; 15:4393. [PMID: 39910105 PMCID: PMC11799152 DOI: 10.1038/s41598-025-88307-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 01/28/2025] [Indexed: 02/07/2025] Open
Abstract
Despite the current diagnostic and therapeutic approaches to bladder cancer being widely accepted, there have been few significant advancements in this field over the past decades. This underscores the necessity for a paradigm shift in the approach to bladder cancer. The role of amyloids in cancer remains unclear despite their identification in several other pathologies. In this study, we present evidence of amyloids in bladder cancer, both in vitro and in vivo. In a murine model of bladder cancer, a positive correlation was observed between amyloids and tumor stage, indicating an association between amyloids and bladder cancer progression. Subsequently, the amyloid proteome of the RT4 non-invasive and HT1197 invasive bladder cancer cell lines was identified and included oncogenes, tumor suppressors, and highly expressed cancer-related proteins. It is proposed that amyloids function as structures that sequester key proteins. Therefore, amyloids should be considered in the study and diagnosis of bladder cancer.
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Affiliation(s)
- Diego Alem
- Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
| | - César X García-Laviña
- Sección Bioquímica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Francisco Garagorry
- Cátedra de Anatomía Patológica, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Dardo Centurión
- Cátedra de Anatomía Patológica, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Joaquina Farias
- Espacio de Biología Vegetal del Noreste, CENUR Noreste, Universidad de la República, Tacuarembó, Uruguay
| | - Hany Pazos-Espinosa
- Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
| | | | - Carolina Villadóniga
- Laboratorio de Biocatalizadores y sus Aplicaciones, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Susana Castro-Sowinski
- Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
- Sección Bioquímica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
- Laboratorio de Biocatalizadores y sus Aplicaciones, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Martín Fló
- Laboratorio de Inmunovirología, Institut Pasteur de Montevideo, Montevideo, Uruguay
- Unidad Académica Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Federico Carrión
- Laboratorio de Inmunovirología, Institut Pasteur de Montevideo, Montevideo, Uruguay
- Unidad de Biofísica de Proteínas, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Brenda Iglesias
- Research Technologies, Research Operations and Externalization, GSK-R&D, Boston, USA
| | - Kevin Madauss
- Research Technologies, Research Operations and Externalization, GSK-R&D, Boston, USA
| | - Lucía Canclini
- Departamento de Genética, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
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2
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Joyce R, Visvader JE. Cells-of-Origin of Breast Cancer and Intertumoral Heterogeneity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:151-165. [PMID: 39821025 DOI: 10.1007/978-3-031-70875-6_9] [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
Both intrinsic and extrinsic mechanisms underpin the profound intertumoral heterogeneity in breast cancer. Increasing evidence suggests that the intrinsic characteristics of breast epithelial precursor cells may influence tumour phenotype. These "cells-of-origin" of cancer preside in normal breast tissue and are uniquely susceptible to mutagenesis upon exposure to distinct oncogenic stimuli. Notably, molecular profiling studies have revealed strong concordance between the gene expression profiles of breast cancer subtypes and discrete cell types within the normal breast epithelium. Further characterisation of cells-of-origin of breast cancer requires comprehensive delineation of the normal mammary stem cell hierarchy. To this end, mouse models have provided valuable tools for exploring stem and progenitor cell function and identifying potential targets of neoplastic transformation via in vivo lineage-tracing studies. Nonetheless, the murine mammary differentiation hierarchy does not fully recapitulate human biology, and complementary studies using patient-direct breast tissue are critical. There is also accumulating evidence that extrinsic factors such as the microenvironment of premalignant cells can influence tumour initiation, highlighting opportunities for targeting cancer cells-of-origin via deconvolution of the premalignant epithelial niche. Pertinently, the identification of premalignant clones and targetable molecular perturbations responsible for driving their oncogenic transformation has critical implications for disease management and prevention.
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Affiliation(s)
- Rachel Joyce
- Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Wurundjeri Country, Melbourne, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Wurundjeri Country, Melbourne, Australia
| | - Jane E Visvader
- Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Wurundjeri Country, Melbourne, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Wurundjeri Country, Melbourne, Australia.
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3
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Majima K, Kojima Y, Minoura K, Abe K, Hirose H, Shimamura T. LineageVAE: reconstructing historical cell states and transcriptomes toward unobserved progenitors. Bioinformatics 2024; 40:btae520. [PMID: 39172488 PMCID: PMC11494380 DOI: 10.1093/bioinformatics/btae520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/22/2024] [Accepted: 08/20/2024] [Indexed: 08/23/2024] Open
Abstract
MOTIVATION Single-cell RNA sequencing (scRNA-seq) enables comprehensive characterization of the cell state. However, its destructive nature prohibits measuring gene expression changes during dynamic processes such as embryogenesis or cell state divergence due to injury or disease. Although recent studies integrating scRNA-seq with lineage tracing have provided clonal insights between progenitor and mature cells, challenges remain. Because of their experimental nature, observations are sparse, and cells observed in the early state are not the exact progenitors of cells observed at later time points. To overcome these limitations, we developed LineageVAE, a novel computational methodology that utilizes deep learning based on the property that cells sharing barcodes have identical progenitors. RESULTS LineageVAE is a deep generative model that transforms scRNA-seq observations with identical lineage barcodes into sequential trajectories toward a common progenitor in a latent cell state space. This method enables the reconstruction of unobservable cell state transitions, historical transcriptomes, and regulatory dynamics at a single-cell resolution. Applied to hematopoiesis and reprogrammed fibroblast datasets, LineageVAE demonstrated its ability to restore backward cell state transitions and infer progenitor heterogeneity and transcription factor activity along differentiation trajectories. AVAILABILITY AND IMPLEMENTATION The LineageVAE model was implemented in Python using the PyTorch deep learning library. The code is available on GitHub at https://github.com/LzrRacer/LineageVAE/.
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Affiliation(s)
- Koichiro Majima
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kojima
- Laboratory of Computational Life Science, National Cancer Center Research Institute, Tokyo, Tokyo 104-0045, Japan
| | - Kodai Minoura
- Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi 466-8550, Japan
| | - Ko Abe
- Department of Computational and Systems Biology, Tokyo Medical and Dental University Medical Research Institute, Tokyo, Tokyo 113-8510, Japan
| | - Haruka Hirose
- Department of Computational and Systems Biology, Tokyo Medical and Dental University Medical Research Institute, Tokyo, Tokyo 113-8510, Japan
| | - Teppei Shimamura
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
- Department of Computational and Systems Biology, Tokyo Medical and Dental University Medical Research Institute, Tokyo, Tokyo 113-8510, Japan
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4
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Giusti V, Miserocchi G, Sbanchi G, Pannella M, Hattinger CM, Cesari M, Fantoni L, Guerrieri AN, Bellotti C, De Vita A, Spadazzi C, Donati DM, Torsello M, Lucarelli E, Ibrahim T, Mercatali L. Xenografting Human Musculoskeletal Sarcomas in Mice, Chick Embryo, and Zebrafish: How to Boost Translational Research. Biomedicines 2024; 12:1921. [PMID: 39200384 PMCID: PMC11352184 DOI: 10.3390/biomedicines12081921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
Musculoskeletal sarcomas pose major challenges to researchers and clinicians due to their rarity and heterogeneity. Xenografting human cells or tumor fragments in rodents is a mainstay for the generation of cancer models and for the preclinical trial of novel drugs. Lately, though, technical, intrinsic and ethical concerns together with stricter regulations have significantly curbed the employment of murine patient-derived xenografts (mPDX). In alternatives to murine PDXs, researchers have focused on embryonal systems such as chorioallantoic membrane (CAM) and zebrafish embryos. These systems are time- and cost-effective hosts for tumor fragments and near-patient cells. The CAM of the chick embryo represents a unique vascularized environment to host xenografts with high engraftment rates, allowing for ease of visualization and molecular detection of metastatic cells. Thanks to the transparency of the larvae, zebrafish allow for the tracking of tumor development and metastatization, enabling high-throughput drug screening. This review will focus on xenograft models of musculoskeletal sarcomas to highlight the intrinsic and technically distinctive features of the different hosts, and how they can be exploited to elucidate biological mechanisms beneath the different phases of the tumor's natural history and in drug development. Ultimately, the review suggests the combination of different models as an advantageous approach to boost basic and translational research.
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Affiliation(s)
- Veronica Giusti
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Giacomo Miserocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (G.M.); (A.D.V.); (C.S.)
| | - Giulia Sbanchi
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Micaela Pannella
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Claudia Maria Hattinger
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Marilena Cesari
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Leonardo Fantoni
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
| | - Ania Naila Guerrieri
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Chiara Bellotti
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Alessandro De Vita
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (G.M.); (A.D.V.); (C.S.)
| | - Chiara Spadazzi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (G.M.); (A.D.V.); (C.S.)
| | - Davide Maria Donati
- Orthopaedic Oncology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Monica Torsello
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Enrico Lucarelli
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Toni Ibrahim
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
| | - Laura Mercatali
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (V.G.); (G.S.); (M.P.); (C.M.H.); (M.C.); (L.F.); (A.N.G.); (C.B.); (T.I.); (L.M.)
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5
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Jiao J, Wu P. A meta-analysis on the potency of foot-and-mouth disease vaccines in different animal models. Sci Rep 2024; 14:8931. [PMID: 38637656 PMCID: PMC11026367 DOI: 10.1038/s41598-024-59755-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 04/15/2024] [Indexed: 04/20/2024] Open
Abstract
Whether mice can be used as a foot-and-mouth disease (FMD) model has been debated for a long time. However, the major histocompatibility complex between pigs and mice is very different. In this study, the protective effects of FMD vaccines in different animal models were analyzed by a meta-analysis. The databases PubMed, China Knowledge Infrastructure, EMBASE, and Baidu Academic were searched. For this purpose, we evaluated evidence from 14 studies that included 869 animals with FMD vaccines. A random effects model was used to combine effects using Review Manager 5.4 software. A forest plot showed that the protective effects in pigs were statistically non-significant from those in mice [MH = 0.56, 90% CI (0.20, 1.53), P = 0.26]. The protective effects in pigs were also statistically non-significant from those in guinea pigs [MH = 0.67, 95% CI (0.37, 1.21), P = 0.18] and suckling mice [MH = 1.70, 95% CI (0.10, 28.08), P = 0.71]. Non-inferiority test could provide a hypothesis that the models (mice, suckling mice and guinea pigs) could replace pigs as FMDV vaccine models to test the protective effect of the vaccine. Strict standard procedures should be established to promote the assumption that mice and guinea pigs should replace pigs in vaccine evaluation.
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Affiliation(s)
- Jiao Jiao
- College of Life Sciences, Shihezi University, Shihezi, China
- Ministry of Education Key Laboratory of Xinjiang Phytomedicine Resource Utilization, Shihezi, China
- Xinjiang Production and Construction Corps Key Laboratory of Oasis Town and Mountain-Basin System Ecology, Shihezi, China
| | - Peng Wu
- College of Life Sciences, Shihezi University, Shihezi, China.
- Ministry of Education Key Laboratory of Xinjiang Phytomedicine Resource Utilization, Shihezi, China.
- Xinjiang Production and Construction Corps Key Laboratory of Oasis Town and Mountain-Basin System Ecology, Shihezi, China.
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6
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Kan C, Tan Z, Liu L, Liu B, Zhan L, Zhu J, Li X, Lin K, Liu J, Liu Y, Yang F, Wong M, Wang S, Zheng H. Phase separation of SHP2E76K promotes malignant transformation of mesenchymal stem cells by activating mitochondrial complexes. JCI Insight 2024; 9:e170340. [PMID: 38451719 PMCID: PMC11141883 DOI: 10.1172/jci.insight.170340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/05/2024] [Indexed: 03/09/2024] Open
Abstract
Mesenchymal stem cells (MSCs), suffering from diverse gene hits, undergo malignant transformation and aberrant osteochondral differentiation. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a nonreceptor protein tyrosine phosphatase, regulates multicellular differentiation, proliferation, and transformation. However, the role of SHP2 in MSC fate determination remains unclear. Here, we showed that MSCs bearing the activating SHP2E76K mutation underwent malignant transformation into sarcoma stem-like cells. We revealed that the SHP2E76K mutation in mouse MSCs led to hyperactive mitochondrial metabolism by activating mitochondrial complexes I and III. Inhibition of complexes I and III prevented hyperactive mitochondrial metabolism and malignant transformation of SHP2E76K MSCs. Mechanistically, we verified that SHP2 underwent liquid-liquid phase separation (LLPS) in SHP2E76K MSCs. SHP2 LLPS led to its dissociation from complexes I and III, causing their hyperactivation. Blockade of SHP2 LLPS by LLPS-defective mutations or allosteric inhibitors suppressed complex I and III hyperactivation as well as malignant transformation of SHP2E76K MSCs. These findings reveal that complex I and III hyperactivation driven by SHP2 LLPS promotes malignant transformation of SHP2E76K MSCs and suggest that inhibition of SHP2 LLPS could be a potential therapeutic target for the treatment of activated SHP2-associated cancers.
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Affiliation(s)
- Chen Kan
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Zhenya Tan
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Liwei Liu
- Department of Pathogen Biology and Immunology, School of Medical Technology, Anhui Medical College, Hefei, China
| | - Bo Liu
- Department of Cell Center, 901st Hospital of PLA Joint Logistic Support Force, Anhui, Hefei, China
| | - Li Zhan
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Jicheng Zhu
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Xiaofei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Keqiong Lin
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Jia Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Yakun Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Fan Yang
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Mandy Wong
- Department of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Siying Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
| | - Hong Zheng
- Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China
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7
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Xiong H, Wilson BA, Ge X, Gao X, Cai Q, Xu X, Bachoo R, Qin Z. Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles. NANO LETTERS 2024; 24:1570-1578. [PMID: 38287297 DOI: 10.1021/acs.nanolett.3c04101] [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: 01/31/2024]
Abstract
Glioblastoma (GBM) is the most complex and lethal primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including the angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.
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Affiliation(s)
- Hejian Xiong
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
- Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
| | - Blake A Wilson
- Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
| | - Xiaoqian Ge
- Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
- Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Xiaofei Gao
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Qi Cai
- Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, Louisiana 70803, United States
| | - Xueqi Xu
- Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
| | - Robert Bachoo
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Zhenpeng Qin
- Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
- Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Bioengineering, The University of Texas at Dallas, Richardson, Texas 75080, United States
- Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas 75080, United States
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8
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Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H, Salehian-Dehkordi H, Abdolvand M, Salmanizadeh S, Rashidi M, Niazmand A, Ahmadi S, Feizbakhshan S, Kabiri S, Vatandoost N, Ranjbarnejad T. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer 2023; 22:189. [PMID: 38017433 PMCID: PMC10683363 DOI: 10.1186/s12943-023-01873-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/27/2023] [Indexed: 11/30/2023] Open
Abstract
The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
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Affiliation(s)
- Matin Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fereshteh Behdarvand Dehkordi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Mohammad Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran.
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Hamidreza Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | | | - Mohammad Abdolvand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Sharareh Salmanizadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar-Jereeb Street, Isfahan, 81746-73441, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saba Ahmadi
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
| | - Sara Feizbakhshan
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saber Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Nasimeh Vatandoost
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tayebeh Ranjbarnejad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
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9
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Xiong H, Wilson BA, Ge X, Gao X, Cai Q, Xu X, Bachoo R, Qin Z. Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.29.564569. [PMID: 37961149 PMCID: PMC10634930 DOI: 10.1101/2023.10.29.564569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Glioblastoma (GBM) is the most complex and lethal adult primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that the tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.
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10
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Grasso G, Colella F, Forciniti S, Onesto V, Iuele H, Siciliano AC, Carnevali F, Chandra A, Gigli G, Del Mercato LL. Fluorescent nano- and microparticles for sensing cellular microenvironment: past, present and future applications. NANOSCALE ADVANCES 2023; 5:4311-4336. [PMID: 37638162 PMCID: PMC10448310 DOI: 10.1039/d3na00218g] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/13/2023] [Indexed: 08/29/2023]
Abstract
The tumor microenvironment (TME) demonstrates distinct hallmarks, including acidosis, hypoxia, reactive oxygen species (ROS) generation, and altered ion fluxes, which are crucial targets for early cancer biomarker detection, tumor diagnosis, and therapeutic strategies. Various imaging and sensing techniques have been developed and employed in both research and clinical settings to visualize and monitor cellular and TME dynamics. Among these, ratiometric fluorescence-based sensors have emerged as powerful analytical tools, providing precise and sensitive insights into TME and enabling real-time detection and tracking of dynamic changes. In this comprehensive review, we discuss the latest advancements in ratiometric fluorescent probes designed for the optical mapping of pH, oxygen, ROS, ions, and biomarkers within the TME. We elucidate their structural designs and sensing mechanisms as well as their applications in in vitro and in vivo detection. Furthermore, we explore integrated sensing platforms that reveal the spatiotemporal behavior of complex tumor cultures, highlighting the potential of high-resolution imaging techniques combined with computational methods. This review aims to provide a solid foundation for understanding the current state of the art and the future potential of fluorescent nano- and microparticles in the field of cellular microenvironment sensing.
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Affiliation(s)
- Giuliana Grasso
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Francesco Colella
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
- Department of Mathematics and Physics ''Ennio De Giorgi", University of Salento c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Stefania Forciniti
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Valentina Onesto
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Helena Iuele
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Anna Chiara Siciliano
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
- Department of Mathematics and Physics ''Ennio De Giorgi", University of Salento c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Federica Carnevali
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
- Department of Mathematics and Physics ''Ennio De Giorgi", University of Salento c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Anil Chandra
- Centre for Research in Pure and Applied Sciences, Jain (Deemed-to-be-university) Bangalore Karnataka 560078 India
| | - Giuseppe Gigli
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
- Department of Mathematics and Physics ''Ennio De Giorgi", University of Salento c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
| | - Loretta L Del Mercato
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC) c/o Campus Ecotekne, via Monteroni 73100 Lecce Italy
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11
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Jiang X, Oyang L, Peng Q, Liu Q, Xu X, Wu N, Tan S, Yang W, Han Y, Lin J, Xia L, Peng M, Tang Y, Luo X, Su M, Shi Y, Zhou Y, Liao Q. Organoids: opportunities and challenges of cancer therapy. Front Cell Dev Biol 2023; 11:1232528. [PMID: 37576596 PMCID: PMC10413981 DOI: 10.3389/fcell.2023.1232528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/18/2023] [Indexed: 08/15/2023] Open
Abstract
Organoids are a class of multicellular structures with the capability of self-organizing and the characteristic of original tissues, they are generated from stem cells in 3D culture in vitro. Organoids can mimic the occurrence and progression of original tissues and widely used in disease models in recent years. The ability of tumor organoids to retain characteristic of original tumors make them unique for tumorigenesis and cancer therapy. However, the history of organoid development and the application of organoid technology in cancer therapy are not well understood. In this paper, we reviewed the history of organoids development, the culture methods of tumor organoids establishing and the applications of organoids in cancer research for better understanding the process of tumor development and providing better strategies for cancer therapy. The standardization of organoids cultivation facilitated the large-scale production of tumor organoids. Moreover, it was found that combination of tumor organoids and other cells such as immune cells, fibroblasts and nervous cells would better mimic the microenvironment of tumor progression. This might be important developing directions for tumor organoids in the future.
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Affiliation(s)
- Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Qiang Liu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Xuemeng Xu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wenjuan Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yaqian Han
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Yanyan Tang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Xia Luo
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Min Su
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Yingrui Shi
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, China
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12
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Ahmed T. Biomaterial-based in vitro 3D modeling of glioblastoma multiforme. CANCER PATHOGENESIS AND THERAPY 2023; 1:177-194. [PMID: 38327839 PMCID: PMC10846340 DOI: 10.1016/j.cpt.2023.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/24/2022] [Accepted: 01/04/2023] [Indexed: 02/09/2024]
Abstract
Adult-onset brain cancers, such as glioblastomas, are particularly lethal. People with glioblastoma multiforme (GBM) do not anticipate living for more than 15 months if there is no cure. The results of conventional treatments over the past 20 years have been underwhelming. Tumor aggressiveness, location, and lack of systemic therapies that can penetrate the blood-brain barrier are all contributing factors. For GBM treatments that appear promising in preclinical studies, there is a considerable rate of failure in phase I and II clinical trials. Unfortunately, access becomes impossible due to the intricate architecture of tumors. In vitro, bioengineered cancer models are currently being used by researchers to study disease development, test novel therapies, and advance specialized medications. Many different techniques for creating in vitro systems have arisen over the past few decades due to developments in cellular and tissue engineering. Later-stage research may yield better results if in vitro models that resemble brain tissue and the blood-brain barrier are used. With the use of 3D preclinical models made available by biomaterials, researchers have discovered that it is possible to overcome these limitations. Innovative in vitro models for the treatment of GBM are possible using biomaterials and novel drug carriers. This review discusses the benefits and drawbacks of 3D in vitro glioblastoma modeling systems.
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Affiliation(s)
- Tanvir Ahmed
- Department of Pharmaceutical Sciences, North South University, Bashundhara, Dhaka, 1229, Bangladesh
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13
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Zhou S, Li L, Zhang M, Qin Y, Li B. The function of brother of the regulator of imprinted sites in cancer development. Cancer Gene Ther 2023; 30:236-244. [PMID: 36376421 DOI: 10.1038/s41417-022-00556-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/13/2022] [Accepted: 10/20/2022] [Indexed: 11/15/2022]
Abstract
As Douglas Hanahan and Robert Weinberg compiled, there are nine hallmarks of cancer that are conducive to cancer cell development and survival. Previous studies showed that brother of the regulator of imprinted sites (BORIS) might promote cancer progression through these aspects. The competition between BORIS and CCCTC-binding factor (CTCF), which is crucial in the formation of chromatin loops, affects the normal function of CTCF and leads to neoplasia and deformity. In addition, BORIS belongs to the cancer-testis antigen families, which are potential targets in cancer diagnosis and treatment. Herein, we discuss the function and mechanisms of BORIS, especially in cancer development.
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Affiliation(s)
- Siqi Zhou
- Department of Liver Surgery, West China Hospital, Sichuan University Medical School, 37 Guo Xue Road, Chengdu, 610041, Sichuan Province, China
| | - Lian Li
- Department of Liver Surgery, West China Hospital, Sichuan University Medical School, 37 Guo Xue Road, Chengdu, 610041, Sichuan Province, China
| | - Ming Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University Medical School, 37 Guo Xue Road, Chengdu, 610041, Sichuan Province, China
| | - Yang Qin
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu, 610041, Sichuan Province, China.
| | - Bo Li
- Department of Liver Surgery, West China Hospital, Sichuan University Medical School, 37 Guo Xue Road, Chengdu, 610041, Sichuan Province, China.
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14
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Xu W, Yang S, Lu L, Xu Q, Wu S, Zhou J, Lu J, Fan X, Meng N, Ding Y, Zheng X, Lu W. Influence of lung cancer model characteristics on tumor targeting behavior of nanodrugs. J Control Release 2023; 354:538-553. [PMID: 36641120 DOI: 10.1016/j.jconrel.2023.01.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 01/16/2023]
Abstract
Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.
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Affiliation(s)
- Weixia Xu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Shengmin Yang
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Linwei Lu
- The Department of Integrative Medicine, Huashan Hospital, Fudan University, and The Institutes of Integrative Medicine of Fudan University, Shanghai 200040, China
| | - Qianzhu Xu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Sunyi Wu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Jianfen Zhou
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Jiashen Lu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Xingyan Fan
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Nana Meng
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Yuan Ding
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Xudong Zheng
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China
| | - Weiyue Lu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China; The Department of Integrative Medicine, Huashan Hospital, Fudan University, and The Institutes of Integrative Medicine of Fudan University, Shanghai 200040, China; Shanghai Engineering Research Center of Pharmaceutical Intelligent Equipment, Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Non-Coding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, 333 Longteng Rd., Shanghai 201620, China.
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15
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Wu X, Shi M, Lian Y, Zhang H. Exosomal circRNAs as promising liquid biopsy biomarkers for glioma. Front Immunol 2023; 14:1039084. [PMID: 37122733 PMCID: PMC10140329 DOI: 10.3389/fimmu.2023.1039084] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 03/30/2023] [Indexed: 05/02/2023] Open
Abstract
Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression.
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Affiliation(s)
- Xiaoke Wu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengmeng Shi
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yajun Lian
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Haifeng Zhang, ; Yajun Lian,
| | - Haifeng Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Haifeng Zhang, ; Yajun Lian,
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16
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Maciak S. Cell size, body size and Peto's paradox. BMC Ecol Evol 2022; 22:142. [PMID: 36513976 PMCID: PMC9746147 DOI: 10.1186/s12862-022-02096-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022] Open
Abstract
Carcinogenesis is one of the leading health concerns afflicting presumably every single animal species, including humans. Currently, cancer research expands considerably beyond medicine, becoming a focus in other branches of natural science. Accumulating evidence suggests that a proportional scale of tumor deaths involves domestic and wild animals and poses economical or conservation threats to many species. Therefore, understanding the genetic and physiological mechanisms of cancer initiation and its progression is essential for our future action and contingent prevention. From this perspective, I used an evolutionary-based approach to re-evaluate the baseline for debate around Peto's paradox. First, I review the background of information on which current understanding of Peto's paradox and evolutionary concept of carcinogenesis have been founded. The weak points and limitations of theoretical modeling or indirect reasoning in studies based on intraspecific, comparative studies of carcinogenesis are highlighted. This is then followed by detail discussion of an effect of the body mass in cancer research and the importance of cell size in consideration of body architecture; also, I note to the ambiguity around cell size invariance hypothesis and hard data for variability of cell size across species are provided. Finally, I point to the new research area that is driving concepts to identify exact molecular mechanisms promoting the process of tumorigenesis, which in turn may provide a proximate explanation of Peto's paradox. The novelty of the approach proposed therein lies in intraspecies testing of the effect of differentiation of cell size/number on the probability of carcinogenesis while controlling for the confounding effect of body mass/size.
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Affiliation(s)
- Sebastian Maciak
- grid.25588.320000 0004 0620 6106Department of Evolutionary and Physiological Ecology, Faculty of Biology, University of Białystok, K. Ciołkowskiego 1J, 15-245 Białystok, Poland
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17
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Di Girolamo N, Park M. Cell identity changes in ocular surface Epithelia. Prog Retin Eye Res 2022:101148. [DOI: 10.1016/j.preteyeres.2022.101148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/13/2022] [Accepted: 11/09/2022] [Indexed: 11/21/2022]
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18
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Lee EH, Kim HT, Chun SY, Chung JW, Choi SH, Lee JN, Kim BS, Yoo ES, Kwon TG, Kim TH, Ha YS. Role of the JNK Pathway in Bladder Cancer. Onco Targets Ther 2022; 15:963-971. [PMID: 36091874 PMCID: PMC9462548 DOI: 10.2147/ott.s374908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Abstract
Bladder cancer, one of the most frequently diagnosed cancers worldwide, is associated with high morbidity and mortality and a poor prognosis. The bladder cancer types include 1) non-muscle invasive bladder cancer (NMIBC) and 2) muscle invasive bladder cancer (MIBC). Metastases and chemoresistance in MIBC patients are the leading causes of the high death rate. c-Jun N-terminal kinase (JNK) is an important factor for the undifferentiated state of cancer cells. JNK belongs to the mitogen-activated protein kinases (MAPKs) family; it is activated by various extracellular stimuli, such as stress, radiation, and growth factors and mediates diverse cellular functions, such as apoptosis, autophagy, proliferation, invasion, and migration by mediating AKT (Ak strain transforming), ATG (Autophagy related), mTOR (Mammalian target of rapamycin), and caspases 3, 8, and 9. This review describes the JNK-related functions, mechanisms, and signaling in bladder cancer.
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Affiliation(s)
- Eun Hye Lee
- Joint Institution of Regenerative Medicine, Kyungpook National University, Daegu, Korea
| | - Hyun Tae Kim
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - So Young Chun
- BioMedical Research Institute, Kyungpook National University Hospital, Daegu, Korea
| | - Jae-Wook Chung
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Seock Hwan Choi
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jun Nyung Lee
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Bum Soo Kim
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Eun Sang Yoo
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Tae Gyun Kwon
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Tae-Hwan Kim
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yun-Sok Ha
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
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Nteli P, Bajwa DE, Politakis D, Michalopoulos C, Kefala-Narin A, Efstathopoulos EP, Gazouli M. Nanomedicine approaches for treatment of hematologic and oncologic malignancies. World J Clin Oncol 2022; 13:553-566. [PMID: 36157164 PMCID: PMC9346428 DOI: 10.5306/wjco.v13.i7.553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/10/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is a leading cause of death worldwide. Nowadays, the therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality. Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer. Immunotherapy is revolutionizing cancer treatment, as it can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities (as in the case of the nanodrug Ferumoxytol). Furthermore, the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside. The most common example includes lipid-based nanoparticles that target VEGF-Α and KRAS pathways. This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies. The insights provided and the evidence obtained in this paper indicate a bright future ahead for immuno-oncology applications of engineering nanomedicines.
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Affiliation(s)
- Polyxeni Nteli
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Danae Efremia Bajwa
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Dimitrios Politakis
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Charalampos Michalopoulos
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Anastasia Kefala-Narin
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Efstathios P Efstathopoulos
- 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, General University Hospital Attikon, Athens12462, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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20
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Liu S, Huang F, Ru G, Wang Y, Zhang B, Chen X, Chu L. Mouse Models of Hepatocellular Carcinoma: Classification, Advancement, and Application. Front Oncol 2022; 12:902820. [PMID: 35847898 PMCID: PMC9279915 DOI: 10.3389/fonc.2022.902820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/01/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the subtype of liver cancer with the highest incidence, which is a heterogeneous malignancy with increasing incidence rate and high mortality. For ethical reasons, it is essential to validate medical clinical trials for HCC in animal models before further consideration on humans. Therefore, appropriate models for the study of the pathogenesis of the disease and related treatment methods are necessary. For tumor research, mouse models are the most commonly used and effective in vivo model, which is closer to the real-life environment, and the repeated experiments performed on it are closer to the real situation. Several mouse models of HCC have been developed with different mouse strains, cell lines, tumor sites, and tumor formation methods. In this review, we mainly introduce some mouse HCC models, including induced model, gene-edited model, HCC transplantation model, and other mouse HCC models, and discuss how to choose the appropriate model according to the purpose of the experiments.
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Affiliation(s)
- Sha Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Huang
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Guoqing Ru
- Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Yigang Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Liang Chu,
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21
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Tumor-Associated Inflammation: The Tumor-Promoting Immunity in the Early Stages of Tumorigenesis. J Immunol Res 2022; 2022:3128933. [PMID: 35733919 PMCID: PMC9208911 DOI: 10.1155/2022/3128933] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
Tumorigenesis is a multistage progressive oncogenic process caused by alterations in the structure and expression level of multiple genes. Normal cells are continuously endowed with new capabilities in this evolution, leading to subsequent tumor formation. Immune cells are the most important components of inflammation, which is closely associated with tumorigenesis. There is a broad consensus in cancer research that inflammation and immune response facilitate tumor progression, infiltration, and metastasis via different mechanisms; however, their protumor effects are equally important in tumorigenesis at earlier stages. Previous studies have demonstrated that during the early stages of tumorigenesis, certain immune cells can promote the formation and proliferation of premalignant cells by inducing DNA damage and repair inhibition, releasing trophic/supporting signals, promoting immune escape, and activating inflammasomes, as well as enhance the characteristics of cancer stem cells. In this review, we focus on the potential mechanisms by which immune cells can promote tumor initiation and promotion in the early stages of tumorigenesis; furthermore, we discuss the interaction of the inflammatory environment and protumor immune cells with premalignant cells and cancer stem cells, as well as the possibility of early intervention in tumor formation by targeting these cellular mechanisms.
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22
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Philip BM, John JS, V S, Kuruvilla TK, Paulose TAP, Sajan D. Vibrational spectra and molecular docking studies of bergapten isolated from Melicopedenhamii leaves as anti-breast cancer agents. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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23
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Cellular Model of Malignant Transformation of Primary Human Astrocytes Induced by Deadhesion/Readhesion Cycles. Int J Mol Sci 2022; 23:ijms23094471. [PMID: 35562862 PMCID: PMC9103552 DOI: 10.3390/ijms23094471] [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: 12/01/2021] [Revised: 04/03/2022] [Accepted: 04/12/2022] [Indexed: 01/07/2023] Open
Abstract
Astrocytoma is the most common and aggressive tumor of the central nervous system. Genetic and environmental factors, bacterial infection, and several other factors are known to be involved in gliomagenesis, although the complete underlying molecular mechanism is not fully understood. Tumorigenesis is a multistep process involving initiation, promotion, and progression. We present a human model of malignant astrocyte transformation established by subjecting primary astrocytes from healthy adults to four sequential cycles of forced anchorage impediment (deadhesion). After limiting dilution of the surviving cells obtained after the fourth deadhesion/readhesion cycle, three clones were randomly selected, and exhibited malignant characteristics, including increased proliferation rate and capacity for colony formation, migration, and anchorage-independent growth in soft agar. Functional assay results for these clonal cells, including response to temozolomide, were comparable to U87MG—a human glioblastoma-derived cell lineage—reinforcing malignant cell transformation. RNA-Seq analysis by next-generation sequencing of the transformed clones relative to the primary astrocytes revealed upregulation of genes involved in the PI3K/AKT and Wnt/β-catenin signaling pathways, in addition to upregulation of genes related to epithelial–mesenchymal transition, and downregulation of genes related to aerobic respiration. These findings, at a molecular level, corroborate the change in cell behavior towards mesenchymal-like cell dedifferentiation. This linear progressive model of malignant human astrocyte transformation is unique in that neither genetic manipulation nor treatment with carcinogens are used, representing a promising tool for testing combined therapeutic strategies for glioblastoma patients, and furthering knowledge of astrocytoma transformation and progression.
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24
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Souza AG, Colli LM. Extracellular Vesicles and Interleukins: Novel Frontiers in Diagnostic and Therapeutic for Cancer. Front Immunol 2022; 13:836922. [PMID: 35386696 PMCID: PMC8978938 DOI: 10.3389/fimmu.2022.836922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/25/2022] [Indexed: 12/04/2022] Open
Abstract
Tumor cells present many strategies for survival and dissemination in the tumor environment. Extracellular vesicles are a vital pathway used in crosstalk between tumor and non-malignant cells. They carry different types of molecules that, when internalized by target cells, can activate signaling pathways and molecular processes that will promote and disseminate neoplastic cells. Proteins, nucleic acids, and different cytokines, such as interleukins, are the main classes of molecules carried by extracellular vesicles and are being studied to understand the molecular mechanisms present in the tumor microenvironment. In particular, although poorly understood, the association between EVs and interleukins has revealed potential approaches to the diagnosis and therapeutics of several neoplasms.
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Affiliation(s)
- Aline G Souza
- Department of Medical Imaging, Hematology, and Oncology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Leandro M Colli
- Department of Medical Imaging, Hematology, and Oncology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
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25
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Haraoka Y, Akieda Y, Nagai Y, Mogi C, Ishitani T. Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis. Nat Commun 2022; 13:1417. [PMID: 35304872 PMCID: PMC8933407 DOI: 10.1038/s41467-022-29061-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 02/24/2022] [Indexed: 01/10/2023] Open
Abstract
Most tumours are thought to arise through oncogenic cell generation followed by additional mutations. How a new oncogenic cell primes tumorigenesis by acquiring additional mutations remains unclear. We show that an additional TP53 mutation stimulates primary tumorigenesis by switching oncogene-induced senescence from a tumour suppressor to a driver. Zebrafish imaging reveals that a newly emerged oncogenic cell with the RasG12V mutation becomes senescent and is eliminated from the epithelia, which is prevented by adding a TP53 gain-of-function mutation (TP53R175H) into RasG12V cells. Surviving RasG12V-TP53R175H double-mutant cells senesce and secrete senescence-associated secretory phenotype (SASP)-related inflammatory molecules that convert neighbouring normal cells into SASP factor-secreting senescent cells, generating a heterogeneous tumour-like cell mass. We identify oncogenic cell behaviours that may control the initial human tumorigenesis step. Ras and TP53 mutations and cellular senescence are frequently detected in human tumours; similar switching may occur during the initial step of human tumorigenesis. It is unclear how a single oncogenic cell primes tumorigenesis. Here the authors visualised this behaviour using a zebrafish larval skin as a model and show that RasG12V oncogenic cell is eliminated through oncogene-senescence while a gain of function mutation in p53 alters this behaviour from tumour suppressive to tumour promoting.
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Affiliation(s)
- Yukinari Haraoka
- Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Yuki Akieda
- Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Yuri Nagai
- Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Chihiro Mogi
- Institute for Molecular & Cellular Regulation, Gunma University, Gunma, 371-8512, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan. .,Institute for Molecular & Cellular Regulation, Gunma University, Gunma, 371-8512, Japan. .,Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, 565-0871, Japan.
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26
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An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors. Sci Rep 2022; 12:1275. [PMID: 35075231 PMCID: PMC8786844 DOI: 10.1038/s41598-022-05391-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 01/06/2022] [Indexed: 12/15/2022] Open
Abstract
Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3’-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.
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27
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Takács-Vellai K, Farkas Z, Ősz F, Stewart GW. Model systems in SDHx-related pheochromocytoma/paraganglioma. Cancer Metastasis Rev 2021; 40:1177-1201. [PMID: 34957538 PMCID: PMC8825606 DOI: 10.1007/s10555-021-10009-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/04/2021] [Indexed: 11/17/2022]
Abstract
Pheochromocytoma (PHEO) and paraganglioma (PGL) (together PPGL) are tumors with poor outcomes that arise from neuroendocrine cells in the adrenal gland, and sympathetic and parasympathetic ganglia outside the adrenal gland, respectively. Many follow germline mutations in genes coding for subunits of succinate dehydrogenase (SDH), a tetrameric enzyme in the tricarboxylic acid (TCA) cycle that both converts succinate to fumarate and participates in electron transport. Germline SDH subunit B (SDHB) mutations have a high metastatic potential. Herein, we review the spectrum of model organisms that have contributed hugely to our understanding of SDH dysfunction. In Saccharomyces cerevisiae (yeast), succinate accumulation inhibits alpha-ketoglutarate-dependent dioxygenase enzymes leading to DNA demethylation. In the worm Caenorhabditis elegans, mutated SDH creates developmental abnormalities, metabolic rewiring, an energy deficit and oxygen hypersensitivity (the latter is also found in Drosophila melanogaster). In the zebrafish Danio rerio, sdhb mutants display a shorter lifespan with defective energy metabolism. Recently, SDHB-deficient pheochromocytoma has been cultivated in xenografts and has generated cell lines, which can be traced back to a heterozygous SDHB-deficient rat. We propose that a combination of such models can be efficiently and effectively used in both pathophysiological studies and drug-screening projects in order to find novel strategies in PPGL treatment.
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Affiliation(s)
| | - Zsolt Farkas
- Department of Biological Anthropology, Eötvös Loránd University, Budapest, Hungary
| | - Fanni Ősz
- Department of Biological Anthropology, Eötvös Loránd University, Budapest, Hungary
| | - Gordon W Stewart
- Division of Medicine, University College London, Gower Street, London, WC1E 6BT, UK
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28
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Chen W, Zhou Y, Wu G, Sun P. CCNI2 promotes the progression of human gastric cancer through HDGF. Cancer Cell Int 2021; 21:661. [PMID: 34895232 PMCID: PMC8665640 DOI: 10.1186/s12935-021-02352-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/19/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gastric cancer is a highly aggressive malignant tumor with heterogeneity and is still a global health problem. The present study aimed to investigate the role of Cyclin I-like (CCNI2) in the regulation of phenotype and tumorigenesis, as well as its underlying mechanisms. METHOD The expression profile of CCNI2 in gastric cancer was determined based on The Cancer Genome Atlas (TCGA) database and immunohistochemical staining. The effects of altered CCNI2 expression on the biological phenotypes such as proliferation, clone formation, apoptosis and migration of gastric cancer cell lines BGC-823 and SGC-7901 were investigated. Mice xenograft models were established to reveal the role of CCNI2 knockdown on tumorigenesis. The potential mechanism of CCNI2 regulating gastric cancer was preliminarily determined by RNA sequencing. RESULT CCNI2 was abundantly expressed in gastric cancer and was positively correlated with pathological stage. Knockdown of CCNI2 slowed down the malignant progression of gastric cancer by inhibiting tumor cell proliferation, increasing the susceptibility to apoptosis and suppressing migration. Moreover, downregulation of CCNI2 attenuated the ability of gastric cancer cells to form tumors in mice. Additionally, there was an interaction between CCNI2 and transcription factor hepatoma-derived growth factor (HDGF) in SGC-7901 cells. Knockdown of CCNI2 alleviated the promoting effects of HDGF overexpression in gastric cancer cells. CONCLUSIONS CCNI2 promoted the progression of human gastric cancer through HDGF, which drew further interest regarding its clinical application as a potential therapeutic target.
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Affiliation(s)
- Wenchao Chen
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yang Zhou
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Gang Wu
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.
| | - Peichun Sun
- Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.
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29
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Parekh U, McDonald D, Dailamy A, Wu Y, Cordes T, Zhang K, Tipps A, Metallo C, Mali P. Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas. iScience 2021; 24:103149. [PMID: 34646987 PMCID: PMC8496177 DOI: 10.1016/j.isci.2021.103149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/27/2021] [Accepted: 09/15/2021] [Indexed: 11/22/2022] Open
Abstract
Deconstructing tissue-specific effects of genes and variants on proliferation is critical to understanding cellular transformation and systematically selecting cancer therapeutics. This requires scalable methods for multiplexed genetic screens tracking fitness across time, across lineages, and in a suitable niche, since physiological cues influence functional differences. Towards this, we present an approach, coupling single-cell cancer driver screens in teratomas with hit enrichment by serial teratoma reinjection, to simultaneously screen drivers across multiple lineages in vivo. Using this system, we analyzed population shifts and lineage-specific enrichment for 51 cancer associated genes and variants, profiling over 100,000 cells spanning over 20 lineages, across two rounds of serial reinjection. We confirmed that c-MYC alone or combined with myristoylated AKT1 potently drives proliferation in progenitor neural lineages, demonstrating signatures of malignancy. Additionally, mutant MEK1 S218D/S222D provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis.
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Affiliation(s)
- Udit Parekh
- Department of Electrical and Computer Engineering, University of California San Diego, San Diego, USA
| | - Daniella McDonald
- Department of Bioengineering, University of California San Diego, San Diego, USA
- Biomedical Sciences Graduate Program, University of California San Diego, San Diego, USA
| | - Amir Dailamy
- Department of Bioengineering, University of California San Diego, San Diego, USA
| | - Yan Wu
- Department of Bioengineering, University of California San Diego, San Diego, USA
| | - Thekla Cordes
- Department of Bioengineering, University of California San Diego, San Diego, USA
| | - Kun Zhang
- Department of Bioengineering, University of California San Diego, San Diego, USA
| | - Ann Tipps
- School of Medicine, University of California San Diego, San Diego, USA
| | - Christian Metallo
- Department of Bioengineering, University of California San Diego, San Diego, USA
- Salk Institute of Biological Studies, La Jolla, USA
| | - Prashant Mali
- Department of Bioengineering, University of California San Diego, San Diego, USA
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30
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Khan S, Shin JH, Ferri V, Cheng N, Noel JE, Kuo C, Sunwoo JB, Pratx G. High-resolution positron emission microscopy of patient-derived tumor organoids. Nat Commun 2021; 12:5883. [PMID: 34620852 PMCID: PMC8497512 DOI: 10.1038/s41467-021-26081-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/03/2021] [Indexed: 01/15/2023] Open
Abstract
Tumor organoids offer new opportunities for translational cancer research, but unlike animal models, their broader use is hindered by the lack of clinically relevant imaging endpoints. Here, we present a positron-emission microscopy method for imaging clinical radiotracers in patient-derived tumor organoids with spatial resolution 100-fold better than clinical positron emission tomography (PET). Using this method, we quantify 18F-fluorodeoxyglucose influx to show that patient-derived tumor organoids recapitulate the glycolytic activity of the tumor of origin, and thus, could be used to predict therapeutic response in vitro. Similarly, we measure sodium-iodine symporter activity using 99mTc- pertechnetate and find that the iodine uptake pathway is functionally conserved in organoids derived from thyroid carcinomas. In conclusion, organoids can be imaged using clinical radiotracers, which opens new possibilities for identifying promising drug candidates and radiotracers, personalizing treatment regimens, and incorporating clinical imaging biomarkers in organoid-based co-clinical trials.
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Affiliation(s)
- Syamantak Khan
- Department of Radiation Oncology, Division of Medical Physics, Stanford University School of Medicine, Stanford, USA
| | - June Ho Shin
- Department of Otolaryngology, Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Valentina Ferri
- Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Stanford University School of Medicine, Stanford, CA, USA
| | - Ning Cheng
- Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Julia E Noel
- Department of Otolaryngology, Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Calvin Kuo
- Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - John B Sunwoo
- Department of Otolaryngology, Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Guillem Pratx
- Department of Radiation Oncology, Division of Medical Physics, Stanford University School of Medicine, Stanford, USA.
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31
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Pawlicki JM, Cookmeyer DL, Maseda D, Everett JK, Wei F, Kong H, Zhang Q, Wang HY, Tobias JW, Walter DM, Zullo KM, Javaid S, Watkins A, Wasik MA, Bushman FD, Riley JL. NPM-ALK-Induced Reprogramming of Mature TCR-Stimulated T Cells Results in Dedifferentiation and Malignant Transformation. Cancer Res 2021; 81:3241-3254. [PMID: 33619116 PMCID: PMC8260452 DOI: 10.1158/0008-5472.can-20-2297] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/28/2020] [Accepted: 02/19/2021] [Indexed: 12/22/2022]
Abstract
Fusion genes including NPM-ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM-ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM-ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)-generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations. These findings describe the fundamental mechanisms of NPM-ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation. SIGNIFICANCE: This investigation into malignant transformation of T cells uncovers a requirement for TCR triggering, elucidates integral signaling complexes nucleated by NPM-ALK, and delineates dynamic transcriptional changes as a T cell transforms.See related commentary by Spasevska and Myklebust, p. 3160.
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MESH Headings
- Apoptosis
- Cell Dedifferentiation
- Cell Proliferation
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Cellular Reprogramming
- Humans
- Lymphoma, Large-Cell, Anaplastic/genetics
- Lymphoma, Large-Cell, Anaplastic/immunology
- Lymphoma, Large-Cell, Anaplastic/metabolism
- Lymphoma, Large-Cell, Anaplastic/pathology
- Phosphorylation
- Protein-Tyrosine Kinases/genetics
- Protein-Tyrosine Kinases/metabolism
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- T-Lymphocytes/immunology
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- Jan M Pawlicki
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David L Cookmeyer
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Damian Maseda
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - John K Everett
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Fang Wei
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hong Kong
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Qian Zhang
- Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hong Y Wang
- Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - John W Tobias
- Penn Genomic Analysis Core, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David M Walter
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kelly M Zullo
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sarah Javaid
- Merck Research Laboratories, Boston, Massachusetts
| | | | - Mariusz A Wasik
- Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Frederic D Bushman
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James L Riley
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania.
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
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Zeisig BB, Fung TK, Zarowiecki M, Tsai CT, Luo H, Stanojevic B, Lynn C, Leung AYH, Zuna J, Zaliova M, Bornhauser M, von Bonin M, Lenhard B, Huang S, Mufti GJ, So CWE. Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia. Sci Transl Med 2021; 13:eabc4822. [PMID: 33627486 DOI: 10.1126/scitranslmed.abc4822] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 01/08/2021] [Indexed: 01/13/2023]
Abstract
Chemoresistance remains the major challenge for successful treatment of acute myeloid leukemia (AML). Although recent mouse studies suggest that treatment response of genetically and immunophenotypically indistinguishable AML can be influenced by their different cells of origin, corresponding evidence in human disease is still largely lacking. By combining prospective disease modeling using highly purified human hematopoietic stem or progenitor cells with retrospective deconvolution study of leukemia stem cells (LSCs) from primary patient samples, we identified human hematopoietic stem cells (HSCs) and common myeloid progenitors (CMPs) as two distinctive origins of human AML driven by Mixed Lineage Leukemia (MLL) gene fusions (MLL-AML). Despite LSCs from either MLL-rearranged HSCs or MLL-rearranged CMPs having a mature CD34-/lo/CD38+ immunophenotype in both a humanized mouse model and primary patient samples, the resulting AML cells exhibited contrasting responses to chemotherapy. HSC-derived MLL-AML was highly resistant to chemotherapy and expressed elevated amounts of the multispecific anion transporter ABCC3. Inhibition of ABCC3 by shRNA-mediated knockdown or with small-molecule inhibitor fidaxomicin, currently used for diarrhea associated with Clostridium difficile infection, effectively resensitized HSC-derived MLL-AML toward standard chemotherapeutic drugs. This study not only functionally established two distinctive origins of human LSCs for MLL-AML and their role in mediating chemoresistance but also identified a potential therapeutic avenue for stem cell-associated treatment resistance by repurposing a well-tolerated antidiarrhea drug already used in the clinic.
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Affiliation(s)
- Bernd B Zeisig
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
- Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK
| | - Tsz Kan Fung
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
- Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK
| | - Magdalena Zarowiecki
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
| | - Chiou Tsun Tsai
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
| | - Huacheng Luo
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Boban Stanojevic
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
- Laboratory for Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Science, University of Belgrade, 11000 Belgrade, Serbia
| | - Claire Lynn
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
| | - Anskar Y H Leung
- Department of Medicine, The University of Hong Kong, Pokfulam Road, HKSAR, China
| | - Jan Zuna
- CLIP, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 150 06 Prague 5, Czech Republic
| | - Marketa Zaliova
- CLIP, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 150 06 Prague 5, Czech Republic
| | | | - Malte von Bonin
- Department of Medicine, University Hospital, 01307 Dresden, Germany
| | - Boris Lenhard
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK
- Computational Regulatory Genomics, MRC London Institute of Medical Sciences, London W12 0NN, UK
- Sars International Centre for Marine Molecular Biology, University of Bergen, N-5008 Bergen, Norway
| | - Suming Huang
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
| | - Ghulam J Mufti
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK
- Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK
| | - Chi Wai Eric So
- Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College, London SE5 9NU, UK.
- Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK
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Gonzalez Curto G, Der Vartanian A, Frarma YEM, Manceau L, Baldi L, Prisco S, Elarouci N, Causeret F, Korenkov D, Rigolet M, Aurade F, De Reynies A, Contremoulins V, Relaix F, Faklaris O, Briscoe J, Gilardi-Hebenstreit P, Ribes V. The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition. PLoS Genet 2020; 16:e1009164. [PMID: 33175861 PMCID: PMC7682867 DOI: 10.1371/journal.pgen.1009164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 11/23/2020] [Accepted: 10/02/2020] [Indexed: 12/18/2022] Open
Abstract
The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAX-FOXO1s. Our data demonstrate that PAX-FOXO1s, but not wild-type PAX3 or PAX7, trigger the trans-differentiation of neural cells into FP-RMS-like cells with myogenic characteristics. In parallel, PAX-FOXO1s remodel the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, expression of PAX-FOXO1s, similar to wild-type PAX3/7, reduce the levels of CDK-CYCLIN activity and increase the fraction of cells in G1. Introduction of CYCLIN D1 or MYCN overcomes this PAX-FOXO1-mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism that can explain the apparent limited oncogenicity of PAX-FOXO1 fusion transcription factors. They are also consistent with certain clinical reports indicative of a neural origin of FP-RMS.
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Affiliation(s)
| | | | | | - Line Manceau
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Lorenzo Baldi
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Selene Prisco
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Nabila Elarouci
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Frédéric Causeret
- Université de Paris, Imagine Institute, Team Genetics and Development of the Cerebral Cortex, Paris, France
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Paris, France
| | - Daniil Korenkov
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Muriel Rigolet
- Univ Paris Est Créteil, INSERM, EnVA, EFS, IMRB, Créteil, France
| | - Frédéric Aurade
- Univ Paris Est Créteil, INSERM, EnVA, EFS, IMRB, Créteil, France
- Sorbonne Université, INSERM, UMRS974, Center for Research in Myology, Paris, France
| | - Aurélien De Reynies
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Vincent Contremoulins
- ImagoSeine core facility of Institut Jacques Monod and member of France-BioImaging, France
| | - Frédéric Relaix
- Univ Paris Est Créteil, INSERM, EnVA, EFS, IMRB, Créteil, France
| | - Orestis Faklaris
- ImagoSeine core facility of Institut Jacques Monod and member of France-BioImaging, France
| | - James Briscoe
- The Francis Crick Institute, 1 Midland Road, London, United Kingdom
| | | | - Vanessa Ribes
- Université de Paris, CNRS, Institut Jacques Monod, Paris, France
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Shlapakova TI, Kostin RK, Tyagunova EE. Reactive Oxygen Species: Participation in Cellular Processes and Progression of Pathology. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s1068162020050222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Waas M, Kislinger T. Addressing Cellular Heterogeneity in Cancer through Precision Proteomics. J Proteome Res 2020; 19:3607-3619. [PMID: 32697918 DOI: 10.1021/acs.jproteome.0c00338] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cells exhibit a broad spectrum of functions driven by differences in molecular phenotype. Understanding the heterogeneity between and within cell types has led to advances in our ability to diagnose and manipulate biological systems. Heterogeneity within and between tumors still poses a challenge to the development and efficacy of therapeutics. In this Perspective we review the toolkit of protein-level experimental approaches for investigating cellular heterogeneity. We describe how innovative approaches and technical developments have supported the advent of bottom-up single-cell proteomic analysis and present opportunities and challenges within cancer research. Finally, we introduce the concept of "precision proteomics" and discuss how the advantages and limitations of various experimental approaches render them suitable for different biological systems and questions.
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Shen X, Li Y, He F, Kong J. LncRNA CDKN2B-AS1 Promotes Cell Viability, Migration, and Invasion of Hepatocellular Carcinoma via Sponging miR-424-5p. Cancer Manag Res 2020; 12:6807-6819. [PMID: 32801906 PMCID: PMC7414928 DOI: 10.2147/cmar.s240000] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 06/06/2020] [Indexed: 12/12/2022] Open
Abstract
Objective Hepatocellular carcinoma (HCC) results in high mortality and metastasis. In this study, the effects of long non-coding RNA (lncRNA) CDKN2B-AS1 on the progression of HCC were investigated. Materials and Methods LncRNA CDKN2B-AS1 expression of HCC cancer and adjacent tissues, and HCC cells were detected. Subsequently, CDKN2B-AS1 was overexpressed and silenced in HCC cells to observe the effects of CDKN2B-AS1 on the cell viability, migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cells by performing cell counting kit-8 (CCK-8), wound-healing, Transwell, and Western blot. The target gene of CDKN2B-AS1 was predicted and verified to be miR-424-5p, whose expression in HCC cells with up- or down-regulation of CDKN2B-AS1 expression was determined. Moreover, the effects of miR-424-5p on cell viability, migration, and invasion and EMT of HCC cells were investigated with miR-424-5p up-regulation or down-regulation, together with overexpression or silencing of CDKN2B-AS1. Results CDKN2B-AS1 expression was increased in HCC tissues and cells. Silencing of CDKN2B-AS1 suppressed cell viability, migration, invasion, and EMT, while overexpression of CDKN2B-AS1 produced the opposite results. Furthermore, CDKN2B-AS1 was predicted and verified to target miR-424-5p and was confirmed to negatively modulate miR-424-5p expression. Moreover, overexpression of miR-424-5p partially suppressed the previously high cell viability, migration, and invasion, and activated EMT resulted from up-regulation of CDKN2B-AS1, while silencing of miR-424-5p elevated the cellular processes inhibited by silencing the expression of CDKN2B-AS1. Conclusion The present study revealed that high-expressed CDKN2B-AS1 may associate with the progression of HCC by affecting the cell viability, migration, invasion, and EMT of HCC cells by negatively regulating miR-424-5p.
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Affiliation(s)
- Xinying Shen
- Department of Interventional Radiology, Shenzhen People's Hospital, Shenzhen, Guangdong, People's Republic of China
| | - Yong Li
- Department of Interventional Radiology, Shenzhen People's Hospital, Shenzhen, Guangdong, People's Republic of China
| | - Fan He
- Department of Interventional Radiology, Shenzhen People's Hospital, Shenzhen, Guangdong, People's Republic of China
| | - Jian Kong
- Department of Interventional Radiology, Shenzhen People's Hospital, Shenzhen, Guangdong, People's Republic of China
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Benning L, Peintner A, Finkenzeller G, Peintner L. Automated spheroid generation, drug application and efficacy screening using a deep learning classification: a feasibility study. Sci Rep 2020; 10:11071. [PMID: 32632214 PMCID: PMC7338379 DOI: 10.1038/s41598-020-67960-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
The last two decades saw the establishment of three-dimensional (3D) cell cultures as an acknowledged tool to investigate cell behaviour in a tissue-like environment. Cells growing in spheroids differentiate and develop different characteristics in comparison to their two-dimensionally grown counterparts and are hence seen to exhibit a more in vivo-like phenotype. However, generating, treating and analysing spheroids in high quantities remains labour intensive and therefore limits its applicability in drugs and compound research. Here we present a fully automated pipetting robot that is able to (a) seed hanging drops from single cell suspensions, (b) treat the spheroids formed in these hanging drops with drugs and (c) analyse the viability of the spheroids by an image-based deep learning based convolutional neuronal network (CNN). The model is trained to classify between ‘unaffected’, ‘mildly affected’ and ‘affected’ spheroids after drug exposure. All corresponding spheroids are initially analysed by viability flow cytometry analysis to build a labelled training set for the CNN to subsequently reduce the number of misclassifications. Hence, this approach allows to efficiently examine the efficacy of drug combinatorics or new compounds in 3D cell culture. Additionally, it may provide a valuable instrument to screen for new and individualized systemic therapeutic strategies in second and third line treatment of solid malignancies using patient derived primary cells.
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Affiliation(s)
- Leo Benning
- Department of Plastic and Hand Surgery, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Andreas Peintner
- Department of Computer Science, University of Innsbruck, Innsbruck, Austria
| | - Günter Finkenzeller
- Department of Plastic and Hand Surgery, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Lukas Peintner
- Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, 79104, Freiburg, Germany.
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38
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N-Glycan profiling of lung adenocarcinoma in patients at different stages of disease. Mod Pathol 2020; 33:1146-1156. [PMID: 31907375 DOI: 10.1038/s41379-019-0441-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/03/2019] [Accepted: 11/26/2019] [Indexed: 12/20/2022]
Abstract
Lung adenocarcinoma (LAC) is the most common form of lung cancer that increases in non-smokers at younger age. Altered protein glycosylation is one of the hallmarks of malignancy, its role in cancer progression is still poorly understood. In this study, we report mass spectrometric (MS) analysis of N-glycans released from fresh or defrosted tissue specimens from 24 patients with LAC. Comparison of cancerous versus adjacent healthy tissues revealed substantial differences in N-glycan profiles associated with disease. The significant increase in paucimannose and high-mannose glycans with 6-9 mannose residues and decline in the sialylated complex biantenary core fucosylated glycan with composition NeuAcGal2GlcNAc2Man3GlcNAc2Fuc were general features of tumors. In addition, 42 new N-glycan compositions were detected in cancerous tissues. The prominent changes in advanced disease stages were mostly observed in core fucosylated N-glycans with additional fucose (Fuc) residue/s and enhanced branching with non-galactosylated N-acetyl-glucosamine (GlcNAc) units. Both of these monosaccharide types were linked preferably on the 6-antenna. Importantly, as compared with noncancerous tissues, a number of these significant changes were clearly detectable early on in stage I. Application of N-glycan data obtained from tissues was next assessed and validated for evaluation of small sized biopsies obtained via bronchoscopy. In summary, observed alterations and data of newly detected N-glycans expand knowledge about the glycosylation in LAC and may contribute to research in more tailored therapies. Moreover, the results demonstrate effectiveness of the presented approach for utility in rapid discrimination of cancerous from healthy lung tissues.
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Huang W, Zhu L, Zhao C, Chen X, Cai Z. Integration of proteomics and metabolomics reveals promotion of proliferation by exposure of bisphenol S in human breast epithelial MCF-10A cells. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 712:136453. [PMID: 31945527 DOI: 10.1016/j.scitotenv.2019.136453] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 12/30/2019] [Accepted: 12/30/2019] [Indexed: 06/10/2023]
Abstract
Bisphenol S (BPS) has been reported to have similar estrogenic effects as bisphenol A (BPA). Considering the endocrine disrupting effects of BPS, in this study, we investigated the effects of BPS exposure on normal human breast epithelial cell line MCF-10A by using mass spectrometry (MS)-based metabolomics and quantitative proteomics. We found that exposure to BPS for 24 h altered the proliferation of MCF-10A cells in a hormetic manner with the highest proliferation rate at the dosage of 1 μM. A total of 200 proteins were identified to be significantly changed by 1 μM of BPS exposure. The upregulation of epidermal growth factor receptor (EGFR) and Ras/mTOR-related proteins implied that EGFR-mediated pathways were involved in BPS-induced proliferation of MCF-10A cells. In addition, several proliferation-related protein markers were found to be elevated, such as MKI67 and CDH1, further indicating the promotion of proliferation by low dose of BPS exposure. Besides, 35 endogenous metabolites were found to be significantly changed. The joint pathway analysis of the altered metabolites and proteins suggested changes in pathways of tricarboxylic acid (TCA) cycle, purine metabolism, pyruvate metabolism and lipid metabolism, which were involved in sustaining cell proliferation and cellular signal transduction. Taken together, this study provides insights into the effects and the potential mechanisms of BPS on estrogen receptor α-negative normal breast cell line MCF-10A, broadening our knowledge about the risk of using BPS as the alternative of BPA.
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Affiliation(s)
- Wei Huang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China; Department of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China
| | - Lin Zhu
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Chao Zhao
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Xiangfeng Chen
- Laboratory for Applied Technology of Sophisticated Analytical Instruments, Shandong Analysis and Test Centre, Qilu University of Technology, Shandong, China
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
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Liu X, Sun R, Chen J, Liu L, Cui X, Shen S, Cui G, Ren Z, Yu Z. Crosstalk Mechanisms Between HGF/c-Met Axis and ncRNAs in Malignancy. Front Cell Dev Biol 2020; 8:23. [PMID: 32083078 PMCID: PMC7004951 DOI: 10.3389/fcell.2020.00023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/13/2020] [Indexed: 12/24/2022] Open
Abstract
Several lines of evidence have confirmed the magnitude of crosstalk between HGF/c-Met axis (hepatocyte growth factor and its high-affinity receptor c-mesenchymal-epithelial transition factor) and non-coding RNAs (ncRNAs) in tumorigenesis. Through activating canonical or non-canonical signaling pathways, the HGF/c-Met axis mediates a range of oncogenic processes such as cell proliferation, invasion, apoptosis, and angiogenesis and is increasingly becoming a promising target for cancer therapy. Meanwhile, ncRNAs are a cluster of functional RNA molecules that perform their biological roles at the RNA level and are essential regulators of gene expression. The expression of ncRNAs is cell/tissue/tumor-specific, which makes them excellent candidates for cancer research. Many studies have revealed that ncRNAs play a crucial role in cancer initiation and progression by regulating different downstream genes or signal transduction pathways, including HGF/c-Met axis. In this review, we discuss the regulatory association between ncRNAs and the HGF/c-Met axis by providing a comprehensive understanding of their potential mechanisms and roles in cancer development. These findings could reveal their possible clinical applications as biomarkers for therapeutic interventions.
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Affiliation(s)
- Xin Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianan Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xichun Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shen Shen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Ahmed EY, Abdel Latif NA, El-Mansy MF, Elserwy WS, Abdelhafez OM. VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents. Bioorg Med Chem 2020; 28:115328. [PMID: 31992477 DOI: 10.1016/j.bmc.2020.115328] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 11/19/2019] [Accepted: 01/13/2020] [Indexed: 12/23/2022]
Abstract
Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their in vitro anticancer activity against MCF-7 breast and PC-3 prostate cancer cell lines and were further assessed for their in vitro VEGFR-2 kinase inhibitory activity. The in vitro cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 4a (IC50 = 1.24 µM) and 3d (IC50 = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC50 = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC50 values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 4a and 3d were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 4a, exhibited significant IC50 of 0.36 µM comparable to staurosporine (IC50; 0.33 µM). Moreover, it was capable of inducing preG1 apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 4a, which demonstrated the ability of the tested compound to interact with the key amino acids in the target VEGFR-2 kinase binding site. Additionally, the ADME parameters and physicochemical properties of compound 4a were examined in silico.
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Affiliation(s)
- Eman Y Ahmed
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, Egypt
| | - Nehad A Abdel Latif
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, Egypt
| | - Mohamed F El-Mansy
- Organometallic and Organometalloid Chemistry Department, Chemical Industries Division, National Research Centre, Dokki, Cairo, Egypt
| | - Weam S Elserwy
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, Egypt
| | - Omaima M Abdelhafez
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, Egypt.
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A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes. Proc Natl Acad Sci U S A 2019; 117:563-572. [PMID: 31871155 PMCID: PMC6955337 DOI: 10.1073/pnas.1915770117] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Small cell carcinoma of the bladder (SCCB) is a lethal variant of bladder cancer with no effective treatment. A lack of available preclinical models and clinical cohorts impedes our understanding of its molecular pathogenesis. In this study, we provided a tumor model as functional evidence showing that SCCB and other bladder cancer phenotypes can be derived from normal human urothelial cells. We further demonstrated that SCCB has a distinct transcriptome and identified SCCB-associated cell surface proteins (CSPs) that can be further evaluated as potential therapeutic targets. We show that our model shares CSP profile with clinical SCCB samples. Our findings create a foundation to understand the molecular underpinnings of SCCB and provide tools for developing therapeutic strategies. Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB–up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.
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Liu F, Dai S, Feng D, Peng X, Qin Z, Kearns AC, Huang W, Chen Y, Ergün S, Wang H, Rappaport J, Bryda EC, Chandrasekhar A, Aktas B, Hu H, Chang SL, Gao B, Qin X. Versatile cell ablation tools and their applications to study loss of cell functions. Cell Mol Life Sci 2019; 76:4725-4743. [PMID: 31359086 PMCID: PMC6858955 DOI: 10.1007/s00018-019-03243-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 07/17/2019] [Accepted: 07/22/2019] [Indexed: 12/22/2022]
Abstract
Targeted cell ablation is a powerful approach for studying the role of specific cell populations in a variety of organotypic functions, including cell differentiation, and organ generation and regeneration. Emerging tools for permanently or conditionally ablating targeted cell populations and transiently inhibiting neuronal activities exhibit a diversity of application and utility. Each tool has distinct features, and none can be universally applied to study different cell types in various tissue compartments. Although these tools have been developed for over 30 years, they require additional improvement. Currently, there is no consensus on how to select the tools to answer the specific scientific questions of interest. Selecting the appropriate cell ablation technique to study the function of a targeted cell population is less straightforward than selecting the method to study a gene's functions. In this review, we discuss the features of the various tools for targeted cell ablation and provide recommendations for optimal application of specific approaches.
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Affiliation(s)
- Fengming Liu
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, 70433, USA
- Department of Immunology and Microbiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Shen Dai
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xiao Peng
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
| | - Zhongnan Qin
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, 70433, USA
- Department of Immunology and Microbiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Alison C Kearns
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
| | - Wenfei Huang
- Institute of NeuroImmune Pharmacology, Seton Hall University, 400 South Orange Avenue, South Orange, NJ, 07079, USA
| | - Yong Chen
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
- Key Lab for Immunology in Universities of Shandong Province, School of Clinical Medicine, Weifang Medical University, 261053, Weifang, People's Republic of China
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Julius-Maximillan University, 97070, Wurzburg, Germany
| | - Hong Wang
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA
| | - Jay Rappaport
- Division of Pathology, Tulane National Primate Research Center, 18703 Three Rivers Road, Covington, LA, 70433, USA
| | - Elizabeth C Bryda
- Rat Resource and Research Center, University of Missouri, 4011 Discovery Drive, Columbia, MO, 65201, USA
| | - Anand Chandrasekhar
- Division of Biological Sciences, 340D Life Sciences Center, University of Missouri, 1201 Rollins St, Columbia, MO, USA
| | - Bertal Aktas
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Hongzhen Hu
- Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Sulie L Chang
- Institute of NeuroImmune Pharmacology, Seton Hall University, 400 South Orange Avenue, South Orange, NJ, 07079, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xuebin Qin
- Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA.
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, 70433, USA.
- Department of Immunology and Microbiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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Setia N, Wanjari P, Yassan L, Niu N, Kadri S, Ritterhouse L, Misdraji J, Brown I, Segal J, Hart J. Next-generation sequencing identifies 2 genomically distinct groups among pyloric gland adenomas. Hum Pathol 2019; 97:103-111. [PMID: 31783043 DOI: 10.1016/j.humpath.2019.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/17/2019] [Accepted: 11/19/2019] [Indexed: 12/23/2022]
Abstract
The molecular alterations identified among pyloric gland adenomas (PGAs) in the published literature are based on polymerase chain reaction of targeted genes, and next-generation sequencing (NGS) has not been performed. In this study, we performed NGS and correlated the molecular alterations with the histologic grade of dysplasia and immunohistochemical findings in a cohort of PGAs. Successful DNA extraction and sequencing were performed in 15 pyloric gland adenomas/adenocarcinoma from 12 patients. Additionally, 4 specimens of autoimmune gastritis were selected to serve as the control group. Ten PGAs with low-grade dysplasia were seen to have mutations in the triad of APC, KRAS, and GNAS genes. Five PGAs with high-grade dysplasia/adenocarcinoma exhibited mutations in several genes including APC, CTNNB1, KRAS, GNAS, TP53, CDKN2A, PIK3CA, and EPHA5 genes but did not exhibit mutations in the triad of APC, KRAS, and GNAS genes. The median tumor mutational burden was higher in PGAs with high-grade dysplasia/adenocarcinoma when compared with PGAs with low-grade dysplasia (5.25 and 4.38, respectively). PGAs with high-grade dysplasia/adenocarcinoma had more chromosomal gains and losses than PGAs with low-grade dysplasia. The molecular findings suggest that there are 2 separate mutator pathways of dysplasia development in PGAs.
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Affiliation(s)
- Namrata Setia
- Department of Pathology, University of Chicago, Chicago, 60637, IL, USA.
| | - Pankhuri Wanjari
- Department of Pathology, University of Chicago, Chicago, 60637, IL, USA.
| | - Lindsay Yassan
- Department of Pathology, Rush University, Chicago, 60612, IL, USA.
| | - Nifang Niu
- Department of Pathology, University of Chicago, Chicago, 60637, IL, USA.
| | - Sabah Kadri
- Department of Pathology and Preventive Medicine, Northwestern University, Chicago, 60611, IL, USA.
| | - Lauren Ritterhouse
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
| | - Ian Brown
- Envoi Specialist Pathologists, Brisbane, 4059, QLD, Australia.
| | - Jeremy Segal
- Department of Pathology, University of Chicago, Chicago, 60637, IL, USA.
| | - John Hart
- Department of Pathology, University of Chicago, Chicago, 60637, IL, USA.
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Initiation of human mammary cell tumorigenesis by mutant KRAS requires YAP inactivation. Oncogene 2019; 39:1957-1968. [PMID: 31772328 PMCID: PMC7044112 DOI: 10.1038/s41388-019-1111-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 05/14/2019] [Accepted: 05/27/2019] [Indexed: 01/13/2023]
Abstract
High YAP activity is associated with poor prognosis human breast cancers, but its role during the initial stage of mammary cell transformation is unknown. To address this question, we designed experiments that exploit the ability of KRASG12D-transduced subsets of freshly isolated normal human mammary cells to form invasive tumors rapidly and efficiently when transplanted into immunodeficient mice. Initial examination of the newly developing tumors thus generated revealed a consistent marked loss of nuclear YAP, independent of the initial primary human mammary cell type transduced. Conversely, co-transduction of the same subsets of primary human mammary cells with KRASG12D plus the constitutively active YAPS127A prevented tumor formation. These findings contrast with the enhanced display of transformed properties obtained when the immortalized, but non-tumorigenic MCF10A cells are transduced just with YAPS127A. In addition, we show that YAPS127A-transduction of the human MDA-MB-231 breast cancer cell line (that carry a similar KRAS mutation) enhances their metastatic activity in vivo. We also discover that the KRASG12D-induced early loss of YAP in primary human mammary cells is associated with their induced secretion of amphiregulin. Collectively, these findings suggest that YAP can differentially affect the acquisition of malignant properties by human mammary cells at different stages of their transformation.
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Lima JD, Simoes E, de Castro G, Morais MRP, de Matos‐Neto EM, Alves MJ, Pinto NI, Figueredo RG, Zorn TM, Felipe‐Silva AS, Tokeshi F, Otoch JP, Alcantara P, Cabral FJ, Ferro ES, Laviano A, Seelaender M. Tumour-derived transforming growth factor-β signalling contributes to fibrosis in patients with cancer cachexia. J Cachexia Sarcopenia Muscle 2019; 10:1045-1059. [PMID: 31273954 PMCID: PMC6818454 DOI: 10.1002/jcsm.12441] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 04/05/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro-environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro-environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. METHODS 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. RESULTS Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte-macrophage colony-stimulating factor, interferon-α, and interleukin (IL)-8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight-stable counterparts. Also, IL-8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α-smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)-β1, TGF-β2, and TGF-β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen-activated protein kinase alteration. Hypoxia-inducible factor-1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight-stable group (P = 0.005). CONCLUSIONS Our results demonstrate TGF-β pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF-β-induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.
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Affiliation(s)
- Joanna D.C.C. Lima
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
| | - Estefania Simoes
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
| | - Gabriela de Castro
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
| | - Mychel Raony P.T. Morais
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
| | | | - Michele J. Alves
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
- Department of PathologyOhio State UniversityColumbusOHUSA
| | - Nelson I. Pinto
- Department of PhysiologyFederal University of São PauloSão PauloBrazil
| | - Raquel G. Figueredo
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
| | - Telma M.T. Zorn
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
| | | | - Flavio Tokeshi
- Department of Clinical SurgeryUniversity of São PauloSão PauloBrazil
| | - José P. Otoch
- Department of Clinical SurgeryUniversity of São PauloSão PauloBrazil
| | - Paulo Alcantara
- Department of Clinical SurgeryUniversity of São PauloSão PauloBrazil
| | | | - Emer S. Ferro
- Department of PharmacologyUniversity of São PauloSão PauloBrazil
| | | | - Marilia Seelaender
- Cancer Metabolism Research Group, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
- Department of Clinical SurgeryUniversity of São PauloSão PauloBrazil
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Das A, Barai A, Monteiro M, Kumar S, Sen S. Nuclear softening is essential for protease-independent migration. Matrix Biol 2019; 82:4-19. [DOI: 10.1016/j.matbio.2019.01.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 01/07/2019] [Accepted: 01/07/2019] [Indexed: 02/08/2023]
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Abstract
YAP and TAZ are transcriptional activators pervasively induced in several human solid tumours and their functions in cancer cells are the focus of intense investigation. These studies established that YAP and TAZ are essential to trigger numerous cell-autonomous responses, such as sustained proliferation, cell plasticity, therapy resistance and metastasis. Yet tumours are complex entities, wherein cancer cells are just one of the components of a composite "tumour tissue". The other component, the tumour stroma, is composed of an extracellular matrix with aberrant mechanical properties and other cell types, including cancer-associated fibroblasts and immune cells. The stroma entertains multiple and bidirectional interactions with tumour cells, establishing dependencies essential to unleash tumorigenesis. The molecular players of such interplay remain partially understood. Here, we review the emerging role of YAP and TAZ in choreographing tumour-stromal interactions. YAP and TAZ act within tumour cells to orchestrate responses in stromal cells. Vice versa, YAP and TAZ in stromal cells trigger effects that positively feed back on the growth of tumour cells. Recognizing YAP and TAZ as a hub of the network of signals exchanged within the tumour microenvironment provides a fresh perspective on the molecular principles of tumour self-organization, promising to unveil numerous new vulnerabilities.
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Affiliation(s)
| | | | - Stefano Piccolo
- Department of Molecular Medicine, University of Padova, Padua, Italy.
- IFOM, The FIRC Institute of Molecular Oncology, Padua, Italy.
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Abstract
Large-scale sequencing of human tumours has uncovered a vast array of genomic alterations. Genetically engineered mouse models recapitulate many features of human cancer and have been instrumental in assigning biological meaning to specific cancer-associated alterations. However, their time, cost and labour-intensive nature limits their broad utility; thus, the functional importance of the majority of genomic aberrations in cancer remains unknown. Recent advances have accelerated the functional interrogation of cancer-associated alterations within in vivo models. Specifically, the past few years have seen the emergence of CRISPR-Cas9-based strategies to rapidly generate increasingly complex somatic alterations and the development of multiplexed and quantitative approaches to ascertain gene function in vivo.
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Pellacani D, Tan S, Lefort S, Eaves CJ. Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer. EMBO J 2019; 38:e100330. [PMID: 31304632 PMCID: PMC6627240 DOI: 10.15252/embj.2018100330] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/22/2018] [Accepted: 11/08/2018] [Indexed: 12/18/2022] Open
Abstract
The mammary gland in adult women consists of biologically distinct cell types that differ in their surface phenotypes. Isolation and molecular characterization of these subpopulations of mammary cells have provided extensive insights into their different transcriptional programs and regulation. This information is now serving as a baseline for interpreting the heterogeneous features of human breast cancers. Examination of breast cancer mutational profiles further indicates that most have undergone a complex evolutionary process even before being detected. The consequent intra-tumoral as well as inter-tumoral heterogeneity of these cancers thus poses major challenges to deriving information from early and hence likely pervasive changes in potential therapeutic interest. Recently described reproducible and efficient methods for generating human breast cancers de novo in immunodeficient mice transplanted with genetically altered primary cells now offer a promising alternative to investigate initial stages of human breast cancer development. In this review, we summarize current knowledge about key transcriptional regulatory processes operative in these partially characterized subpopulations of normal human mammary cells and effects of disrupting these processes in experimentally produced human breast cancers.
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Affiliation(s)
- Davide Pellacani
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
| | - Susanna Tan
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
| | - Sylvain Lefort
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
| | - Connie J Eaves
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
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