title: The "go or grow" potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress.
abstract: Glioblastoma (GBM), the most common malignant brain tumor, is among the most lethal neoplasms, with a median survival of approximately 1 year. Prognosis is poor since GBMs possess a strong migratory and highly invasive potential, making complete surgical resection impossible. Reduced expression of carboxypeptidase E (CPE), a neuropeptide-processing enzyme, in a cell death-resistant glioma cell line and lower CPE expression levels in the cohort of GBM samples of The Cancer Genome Atlas compared to normal brain control specimens prompted us to analyze the function of CPE as a putative tumor suppressor gene. In our samples, CPE was also reduced in GBM compared to normal brain with the strongest loss in cells surrounding hypoxic tumor areas as well as in most glioma cell lines and primary glioma cells. In our cohort of glioma patients, loss of CPE predominantly occurred in glioblastomas and was associated with worse prognosis. In glioma cells, CPE overexpression was significantly reduced, whereas knockdown or inhibition enhanced glioma cell migration and invasion. The decreased migratory potential following CPE overexpression was paralleled by altered cellular morphology, promoting a transition to focal adhesions and associated stress fibers. In contrast to the decreased migration, high CPE levels were associated with higher proliferative rates. As microenvironmental regulation cues, we identified CPE as being downregulated upon hypoxia or glucose deprivation. Our findings indicate an oxygen- and nutrition-dependent anti-migratory, but pro-proliferative role of CPE in gliomas with prognostic impact for patient survival, thereby contributing to the understanding of the "go or grow" hypothesis in gliomas.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076, Tübingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Höring
authors.forename: Patrick Nikolaus
authors.initials: PN
authors.lastname: Harter
authors.forename: Janina
authors.initials: J
authors.lastname: Seznec
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Bühring
authors.forename: Shohag
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Elke
authors.initials: E
authors.lastname: von Hattingen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zachskorn
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Ulrike
authors.initials: U
authors.lastname: Naumann
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002232:Carbocyanines / Q000378:metabolism; D043423:Carboxypeptidase H / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D005947:Glucose / Q000172:deficiency; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013386:Succinates / Q000494:pharmacology; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D002232:Carbocyanines; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013386:Succinates; C098830:TO-PRO-3; C022014:guanidinoethylmercaptosuccinic acid; D043423:Carboxypeptidase H; D005947:Glucose