title: Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter.
abstract: Although aerobic glycolysis provides an advantage in the hypoxic tumor microenvironment, some cancer cells can also respire via oxidative phosphorylation. These respiring ("non-Warburg") cells were previously thought not to play a key role in tumorigenesis and thus fell from favor in the literature. We sought to determine whether subpopulations of hypoxic cancer cells have different metabolic phenotypes and gene-expression profiles that could influence tumorigenicity and therapeutic response, and we therefore developed a dual fluorescent protein reporter, HypoxCR, that detects hypoxic [hypoxia-inducible factor (HIF) active] and/or cycling cells. Using HEK293T cells as a model, we identified four distinct hypoxic cell populations by flow cytometry. The non-HIF/noncycling cell population expressed a unique set of genes involved in mitochondrial function. Relative to the other subpopulations, these hypoxic "non-Warburg" cells had highest oxygen consumption rates and mitochondrial capacity consistent with increased mitochondrial respiration. We found that these respiring cells were unexpectedly tumorigenic, suggesting that continued respiration under limiting oxygen conditions may be required for tumorigenicity.
authors.affiliation: Department of Pathology and Oncology, Graduate Program in Pathobiology, dangvchi@exchange.upenn.edu annele@jhmi.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Le
authors.affiliation: Abramson Family Cancer Research Institute, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Zachary E
authors.initials: ZE
authors.lastname: Stine
authors.affiliation: Department of Pathology and Oncology.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Department of Medicine.
authors.forename: Junaid
authors.initials: J
authors.lastname: Afzal
authors.affiliation: Department of Medicine.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Pathology and Oncology.
authors.forename: Max
authors.initials: M
authors.lastname: Hamaker
authors.affiliation: Department of Pathology and Oncology.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Siegel
authors.affiliation: Graduate Program in Pathobiology.
authors.forename: Arvin M
authors.initials: AM
authors.lastname: Gouw
authors.affiliation: Graduate Program in Pathobiology.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Graduate Program in Pathobiology.
authors.forename: Shu-Han
authors.initials: SH
authors.lastname: Yu
authors.affiliation: Graduate Program in Cellular and Molecular Medicine, and.
authors.forename: Rory L
authors.initials: RL
authors.lastname: Cochran
authors.affiliation: Stem Cell Program, Institute for Cell Engineering, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; and.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Sailor
authors.affiliation: Stem Cell Program, Institute for Cell Engineering, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; and.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Pathology and Oncology, Graduate Program in Pathobiology, Abramson Family Cancer Research Institute, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, Graduate Program in Cellular and Molecular Medicine, and dangvchi@exchange.upenn.edu annele@jhmi.edu.
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D019069:Cell Respiration; D015870:Gene Expression; D050259:Genes, Mitochondrial; D017930:Genes, Reporter; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009857:Oncogenes; D010101:Oxygen Consumption
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins
keywords: antiangiogenesis; metabolism; mitochondria
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