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      Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells

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          Abstract

          The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10–35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs and their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.

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          PrognoScan: a new database for meta-analysis of the prognostic value of genes

          Background In cancer research, the association between a gene and clinical outcome suggests the underlying etiology of the disease and consequently can motivate further studies. The recent availability of published cancer microarray datasets with clinical annotation provides the opportunity for linking gene expression to prognosis. However, the data are not easy to access and analyze without an effective analysis platform. Description To take advantage of public resources in full, a database named "PrognoScan" has been developed. This is 1) a large collection of publicly available cancer microarray datasets with clinical annotation, as well as 2) a tool for assessing the biological relationship between gene expression and prognosis. PrognoScan employs the minimum P-value approach for grouping patients for survival analysis that finds the optimal cutpoint in continuous gene expression measurement without prior biological knowledge or assumption and, as a result, enables systematic meta-analysis of multiple datasets. Conclusion PrognoScan provides a powerful platform for evaluating potential tumor markers and therapeutic targets and would accelerate cancer research. The database is publicly accessible at .
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            Hypoxia-inducible factors, stem cells, and cancer.

            Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation. The hypoxia-inducible factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression.
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              Human ATP-binding cassette (ABC) transporter family

              There exist four fundamentally different classes of membrane-bound transport proteins: ion channels; transporters; aquaporins; and ATP-powered pumps. ATP-binding cassette (ABC) transporters are an example of ATP-dependent pumps. ABC transporters are ubiquitous membrane-bound proteins, present in all prokaryotes, as well as plants, fungi, yeast and animals. These pumps can move substrates in (influx) or out (efflux) of cells. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC proteins transport a number of endogenous substrates, including inorganic anions, metal ions, peptides, amino acids, sugars and a large number of hydrophobic compounds and metabolites across the plasma membrane, and also across intracellular membranes. The human genome contains 49 ABC genes, arranged in eight subfamilies and named via divergent evolution. That ABC genes are important is underscored by the fact that mutations in at least I I of these genes are already known to cause severe inherited diseases (eg cystic fibrosis and X-linked adrenoleukodystrophy [X-ALD]). ABC transporters also participate in the movement of most drugs and their metabolites across cell surface and cellular organelle membranes; thus, defects in these genes can be important in terms of cancer therapy, pharmacokinetics and innumerable pharmacogenetic disorders.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                10 October 2018
                2018
                : 8
                : 376
                Affiliations
                [1] 1Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University , Okayama, Japan
                [2] 2Department of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University , Okayama, Japan
                [3] 3Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University , Okayama, Japan
                [4] 4Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University , Okayama, Japan
                [5] 5Department of Oral Diagnosis and Dentomaxillofacial Radiology, Okayama University Hospital , Okayama, Japan
                [6] 6Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, United States
                Author notes

                Edited by: Saverio Marchi, University of Ferrara, Italy

                Reviewed by: Saraswati Sukumar, Johns Hopkins University, United States; Alessandro Rimessi, University of Ferrara, Italy

                *Correspondence: Takanori Eguchi eguchi@ 123456okayama-u.ac.jp

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00376
                6191470
                30364132
                142f64d0-9220-4d0d-be36-30df86b354e7
                Copyright © 2018 Namba, Sogawa, Okusha, Kawai, Itagaki, Ono, Murakami, Aoyama, Ohyama, Asaumi, Takigawa, Okamoto, Calderwood, Kozaki and Eguchi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 April 2018
                : 22 August 2018
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 87, Pages: 16, Words: 11162
                Funding
                Funded by: Japan Society for the Promotion of Science 10.13039/501100001691
                Award ID: JP16K11722
                Award ID: JP17K11642
                Award ID: 17K11643
                Award ID: JP17K11669
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                abcg transporter,abcg1,tumoroids,extracellular vesicle,metastatic cancer,hypoxia

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