title: Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas.
abstract: BACKGROUND
  A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti-vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment.
  
  
  METHODS
  The aim of our study was to determine the expression of VEGF-A and its (co-) receptors by immunohistochemistry and to test the association with patient survival in 350 glioma patients. Additionally, VEGF-A expression was analyzed by in-situ hybridization. In 18 patients, the protein expression was compared with the bevacizumab response according to extended and modified RANO criteria.
  
  
  RESULTS
  We found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal-appearing brain tissue (P < .001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1, -2 and neuropilin-1 levels as compared to WHO grade II and III astrocytomas (P < .01) but at lower levels than glioblastomas. The expression of neuropilin-2 was low in all tumors. There was neither a significant correlation between protein expression and patient survival nor between protein levels and bevacizumab response after modified RANO criteria.
  
  
  CONCLUSIONS
  Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response.
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Anna-Eva
authors.initials: AE
authors.lastname: Blank
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Kea
authors.initials: K
authors.lastname: Franz
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Maika
authors.initials: M
authors.lastname: Dunst
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Pia
authors.initials: P
authors.lastname: Zeiner
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Katharina
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Mäder
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Marcia
authors.initials: M
authors.lastname: Machein
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Volker
authors.initials: V
authors.lastname: Seifert
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (P.B., A.-E.B., M.D., P.Z., K.H., L.M., K.H.P., P.N.H., M.Mi.); Department of Neurosurgery, Goethe University, Frankfurt, Germany (K.F., V.S.); Dr. Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany (K.F., O.B., J.P.S.); Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany (E.H.); Department of Neurosurgery, University Hospital, Freiburg, Germany (M.Ma.); Cancer Consortium (DKTK), Heidelberg, Germany (O.B., J.P.S., K.H.P, P.N.H., M.Mi.); German Cancer Research Center (DKFZ), Heidelberg, Germany (O.B., J.P.S., K.H.P., P.N.H., M.Mi.); Department of Pathology, University of Heidelberg, Heidelberg, Germany (B.G.).
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068258:Bevacizumab / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D039942:Neuropilin-1 / Q000378:metabolism*; D039943:Neuropilin-2 / Q000378:metabolism*; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D039943:Neuropilin-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C581308:neuropilin-2, human; D039942:Neuropilin-1; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: VEGF; VEGF receptors; antiangiogenic therapy; bevacizumab; glioma