title: Exosomal Proteome Profiling: A Potential Multi-Marker Cellular Phenotyping Tool to Characterize Hypoxia-Induced Radiation Resistance in Breast Cancer.
abstract: Radiation and drug resistance are significant challenges in the treatment of locally advanced, recurrent and metastatic breast cancer that contribute to mortality. Clinically, radiotherapy requires oxygen to generate cytotoxic free radicals that cause DNA damage and allow that damage to become fixed in the genome rather than repaired. However, approximately 40% of all breast cancers have hypoxic tumor microenvironments that render cancer cells significantly more resistant to irradiation. Hypoxic stimuli trigger changes in the cell death/survival pathway that lead to increased cellular radiation resistance. As a result, the development of noninvasive strategies to assess tumor hypoxia in breast cancer has recently received considerable attention. Exosomes are secreted nanovesicles that have roles in paracrine signaling during breast tumor progression, including tumor-stromal interactions, activation of proliferative pathways and immunosuppression. The recent development of protocols to isolate and purify exosomes, as well as advances in mass spectrometry-based proteomics have facilitated the comprehensive analysis of exosome content and function. Using these tools, studies have demonstrated that the proteome profiles of tumor-derived exosomes are indicative of the oxygenation status of patient tumors. They have also demonstrated that exosome signaling pathways are potentially targetable drivers of hypoxia-dependent intercellular signaling during tumorigenesis. This article provides an overview of how proteomic tools can be effectively used to characterize exosomes and elucidate fundamental signaling pathways and survival mechanisms underlying hypoxia-mediated radiation resistance in breast cancer.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; sthoma92@jhmi.edu.
authors.forename: Stefani N
authors.initials: SN
authors.lastname: Thomas
authors.affiliation: Eli Lilly and Company, Indianapolis, IN 46285, USA; zliao001@umaryland.edu.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; djclark81@gmail.com (D.C.); yangyic@gmail.com (Y.C.); pshapiro@rx.umaryland.edu (P.S.) ; Division of Oncology, University of Maryland School of Dentistry, Baltimore, MD 21201, USA.
authors.forename: David
authors.initials: D
authors.lastname: Clark
authors.affiliation: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; djclark81@gmail.com (D.C.); yangyic@gmail.com (Y.C.); pshapiro@rx.umaryland.edu (P.S.).
authors.forename: Yangyi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA; rsama002@umaryland.edu.
authors.forename: Ramin
authors.initials: R
authors.lastname: Samadani
authors.affiliation: Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD 21201, USA; LMao@umaryland.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; dann@coh.org ; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
authors.affiliation: Department of Radiation Oncology, University of California, Irvine, CA 92697, USA; jbaulch@uci.edu.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Baulch
authors.affiliation: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; djclark81@gmail.com (D.C.); yangyic@gmail.com (Y.C.); pshapiro@rx.umaryland.edu (P.S.) ; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA; rsama002@umaryland.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Shapiro
authors.affiliation: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; djclark81@gmail.com (D.C.); yangyic@gmail.com (Y.C.); pshapiro@rx.umaryland.edu (P.S.) ; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Yang
keywords: breast cancer; exosomes; hypoxia; proteomics; radiation; tumor microenvironment