title: Cell context-dependent dual effects of EFEMP1 stabilizes subpopulation equilibrium in responding to changes of in vivo growth environment.
abstract: Conflicting functions of EFEMP1 in cancer have been reported. Using two syngeneic glioma cell lines (U251 and U251-NS) carrying two different principal cell subpopulations that express high or low EGFR, and that are able to interconvert via mis-segregation of chromosome 7 (Chr7), we studied EFEMP1's cell-context-dependent functions in regulating subpopulation equilibrium, here defined by the percentage of cells carrying different copies of Chr7. We found that EFEMP1 attenuated levels of EGFR and cellular respiration in high-EGFR-expressing cells, but increased levels of NOTCH1, MMP2, cell invasiveness, and both oxidative phosphorylation and glycolytic respiration in low-EGFR-expressing cells. Consistently, EFEMP1 suppressed intracranial xenograft formation in U251 and promoted its formation in U251-NS. Interestingly, subpopulation equilibria in xenografts of U251-NS without EFEMP1 overexpression were responsive to inoculum size (1, 10 and 100 thousand cells), which may change the tumor-onset environment. It was not observed in xenografts of U251-NS with EFEMP1 overexpression. The anti-EGFR function of EFEMP1 suppressed acceleration of growth of U251-NS, but not the subpopulation equilibrium, when serially passed under a different (serum-containing adherent) culture condition. Overall, the data suggest that the orthotopic environment of the brain tumor supports EFEMP1 in carrying out both its anti-EGFR and pro-invasive/cancer stem cell-transforming functions in the two glioma cell subpopulations during formation of a single tumor, where EFEMP1 stabilizes the subpopulation equilibrium in response to alterations of the growth environment. This finding implies that EFEMP1 may restrain cancer plasticity in coping with ever-changing tumor microenvironments and/or therapeutic-intervention stresses.
authors: Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
authors: Yuanjie
authors: Y
authors: Hu
authors: Department of Surgery, University of California Irvine, Irvine, CA, USA.|State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors: Chao
authors: C
authors: Ke
authors: Department of Surgery, University of California Irvine, Irvine, CA, USA.
authors: Ning
authors: N
authors: Ru
authors: UC Irvine Diabetes Center and Department of Medicine, University of California Irvine, Irvine, CA, USA.
authors: Yumay
authors: Y
authors: Chen
authors: Ziren Research LLC, Irvine, CA, USA.
authors: Liping
authors: L
authors: Yu
authors: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Eric R
authors: ER
authors: Siegel
authors: Department of Surgery, University of California Irvine, Irvine, CA, USA.
authors: Mark E
authors: ME
authors: Linskey
authors: UC Irvine Diabetes Center and Department of Medicine, University of California Irvine, Irvine, CA, USA.
authors: Ping
authors: P
authors: Wang
authors: Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.|Department of Surgery, University of California Irvine, Irvine, CA, USA.
authors: Yi-Hong
authors: YH
authors: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EFEMP1; cell invasiveness; glioma; tumor cell subpopulations; tumor subpopulation equilibrium