title: Metastatic Breast Cancer Cells Enter Into Dormant State and Express Cancer Stem Cells Phenotype Under Chronic Hypoxia.
abstract: Tumor dormancy is a poorly understood stage in cancer progression characterized by mitotic cycle arrest in G0/G1 phase and low metabolism. The cells survive in a quiescent state and wait for appropriate environmental conditions to begin proliferation again giving rise to metastasis. Despite their key role in cancer development and metastasis, the knowledge about their biology and origin is still very limited due to the poorness of established in vitro models that faithfully recapitulated tumor dormancy. Using at least three cycles of 1% O2hypoxia and reoxygenation, we establish and characterize the hypoxia-resistant human breast cancer cell line chMDA-MB-231 that can stably survive under 1% O2condition by entering into dormant state characterized by arrest in G0/G1 phase and low metabolism. This dormant state is reversible since once replaced in normoxia the cells recover the proliferation rate in 2 weeks. We show that chronic hypoxia induces autophagy that may be the survival mechanism of chMDA-MB-231 cells. Furthermore, the data in this work demonstrate that cycling hypoxic/reoxygenation stress selects MDA-MB-231 population that presents the cancer stem-like phenotype characterized by CD24-/CD44+/ESA+expression and spheroid forming capacity. We believe that our study presents a promising approach to select dormant breast cancer cells with stem-like phenotype using the hypoxia/reoxygenation regimen that may represent an area with profound implications for therapeutic developments in oncology. J. Cell. Biochem. 118: 3237-3248, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, Verona, 37134, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carcereri de Prati
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, Verona, 37134, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Butturini
authors.affiliation: Department of Medicine, Section of Hematology, Cancer Research and Cell Biology Laboratory University of Verona, Piazzale Scuro, Verona, 37134, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Rigo
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, Verona, 37134, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Oppici
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, Verona, 37134, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Rossin
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, Verona, 37134, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Boriero
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, Verona, 37134, Italy.
authors.forename: Sofia
authors.identifier: 0000-0002-3629-435X
authors.initials: S
authors.lastname: Mariotto
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D016192:Resting Phase, Cell Cycle
keywords: AUTOPHAGY; CANCER STEM CELLS; CHRONIC HYPOXIA; DORMANCY; TUMORSPHERE