title: Loss of endothelial programmed cell death 10 activates glioblastoma cells and promotes tumor growth.
abstract: BACKGROUND
  Neo-angiogenesis is a hallmark of glioblastoma (GBM) and is sustained by autocrine and paracrine interactions between neoplastic and nonneoplastic cells. Programmed cell death 10 (PDCD10) is ubiquitously expressed in nearly all tissues and plays crucial roles in regulating angiogenesis and apoptosis. We recently discovered the absence of PDCD10 expression in the tumor vessels of GBM patients. This raised the hypothesis that loss of endothelial PDCD10 affected GBM cell phenotyping and tumor progression.
  
  
  METHODS
  Endothelial PDCD10 was silenced by siRNA and lentiviral shRNA. The tumor cell phenotype was studied in direct and indirect co-culture of endothelial cells (ECs) with U87 or LN229. Angiogenic protein array was performed in the media of PDCD10-silenced ECs. Tumor angiogenesis and tumor growth were investigated in a human GBM xenograft mouse model.
  
  
  RESULTS
  Endothelial silence of PDCD10 significantly stimulated tumor cell proliferation, migration, adhesion, and invasion and inhibited apoptosis in co-cultures. Stable knockdown of endothelial PDCD10 increased microvessel density and the formation of a functional vascular network, leading to a 4-fold larger tumor mass in mice. Intriguingly, endothelial deletion of PDCD10 increased (≥2-fold) the release of 20 of 55 tested proangiogenic factors including VEGF, which in turn activated Erk1/2 and Akt in GBM cells.
  
  
  CONCLUSIONS
  For the first time, we provide evidence that loss of endothelial PDCD10 activates GBM cells and promotes tumor growth, most likely via a paracrine mechanism. PDCD10 shows a tumor-suppressor-like function in the cross talk between ECs and tumor cells and is potentially implicated in GBM progression.
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Anja
authors.initials: A
authors.lastname: Prinz
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Nicole
authors.initials: N
authors.lastname: Lambertz
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Ilonka
authors.initials: I
authors.lastname: Kreitschmann-Andermahr
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany (Y.Z., K.Z., A.P., N.L., I.K.-A., U.S.); Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neurosurgery, Tongji Medical College, Wuhan, China (K.Z., T.L.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D040081:Protein Array Analysis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering
keywords: PDCD10/CCM3; angiogenesis; endothelial cells; glioblastoma