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@ARTICLE{Cao:283141,
      author       = {C. Cao and L. Zhang and M. D. Sorensen and G.
                      Reifenberger$^*$ and B. W. Kristensen and T. M. McIntyre and
                      F. Lin},
      title        = {{D}-2-hydroxyglutarate regulates human brain vascular
                      endothelial cell proliferation and barrier function.},
      journal      = {Journal of neuropathology and experimental neurology},
      volume       = {82},
      number       = {11},
      issn         = {0022-3069},
      address      = {Philadelphia, Pa. [u.a.]},
      publisher    = {Lippincott Williams $\&$ Wilkins},
      reportid     = {DKFZ-2023-01928},
      pages        = {921-933},
      year         = {2023},
      note         = {2023 Oct 20;82(11):921-933},
      abstract     = {Gain-of-function mutations in isocitrate dehydrogenase
                      (IDH) genes result in excessive production of
                      (D)-2-hydroxyglutarate (D-2HG) which intrinsically modifies
                      tumor cell epigenetics and impacts surrounding noncancerous
                      cells through nonepigenetic pathways. However, whether D-2HG
                      has a paracrine effect on endothelial cells in the tumor
                      microenvironment needs further clarification. We quantified
                      microvessel density by immunohistochemistry using tissue
                      sections from 60 high-grade astrocytic gliomas with or
                      without IDH mutation. Microvessel density was found to be
                      reduced in tumors carrying an IDH mutation. Ex vivo
                      experiments showed that D-2HG inhibited endothelial cell
                      migration, wound healing, and tube formation by suppressing
                      cell proliferation but not viability, possibly through
                      reduced activation of the mTOR/STAT3 pathway. Further, D-2HG
                      reduced fluorescent dextran permeability and decreased
                      paracellular T-cell transendothelial migration by augmenting
                      expression of junctional proteins thereby collectively
                      increasing endothelial barrier function. These results
                      indicate that D-2HG may influence the tumor vascular
                      microenvironment by reducing the intratumoral vasculature
                      density and by inhibiting the transport of metabolites and
                      extravasation of circulating cells into the astrocytoma
                      microenvironment. These observations provide a rationale for
                      combining IDH inhibition with antitumor
                      immunological/angiogenic approaches and suggest a molecular
                      basis for resistance to antiangiogenic drugs in patients
                      whose tumors express a mutant IDH allele.},
      keywords     = {(D)-2-hydroxyglutarate (D-2HG) (Other) / Astrocytic glioma
                      (Other) / Brain vascular endothelial cell (Other) /
                      Glioblastoma (Other) / Isocitrate dehydrogenase (IDH)
                      (Other) / Microvascular proliferation (Other)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37740942},
      doi          = {10.1093/jnen/nlad072},
      url          = {https://inrepo02.dkfz.de/record/283141},
}