title: Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours.
abstract: BACKGROUND
  Tumour angiogenesis is crucially dependent on the communication between the tumour and the associated endothelium. Protein kinase D (PKD) isoenzymes mediate vascular endothelial growth factor-A (VEGF-A) induced endothelial cell proliferation and migration and are also highly expressed in various tumours.
  
  
  OBJECTIVE
  To examine the role of PKDs for tumour proliferation and angiogenesis selectively in pancreatic and gastric tumours and in tumour-associated endothelium in vitro and in vivo.
  
  
  METHODS
  PKD2 expression in human tumours was determined by immunohistochemistry. The effect of PKD2 depletion in endothelial cells by siRNAs was examined in sprouting assays, the chorioallantois model (CAM) and tumour xenografts. In murine endothelium in vivo PKD2 was knocked-down by splice switching oligonucleotides. Human PKD2 was depleted in xenografts by siRNAs and PKD2-miRs. PKD2 activation by hypoxia and its role for hypoxia-induced NR4/TR3- and VEGF-A promoter activity, expression and secretion was investigated in cell lines.
  
  
  RESULTS
  PKD2 is expressed in gastrointestinal tumours and in the tumour-associated endothelium. Tumour growth and angiogenesis in the CAM and in tumour xenografts require PKD expression in endothelial cells. Conversely, hypoxia activates PKD2 in pancreatic cancer cells and PKD2 was identified as the major mediator of hypoxia-stimulated VEGF-A promoter activity, expression and secretion in tumour cells. PKD2 depletion in pancreatic tumours inhibited tumour-driven blood vessel formation and tumour growth in the CAM and in orthotopic pancreatic cancer xenografts.
  
  
  CONCLUSIONS
  PKD2 regulates hypoxia-induced VEGF-A expression/secretion by tumour cells and VEGF-A stimulated blood vessel formation. PKD2 is a novel, essential mediator of tumour cell-endothelial cell communication and a promising therapeutic target to inhibit angiogenesis in gastrointestinal cancers.
authors: Department of Internal Medicine 1, Division of Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, Halle (Saale), Germany.
authors: Ninel
authors: N
authors: Azoitei
authors: Ganesh Varma
authors: GV
authors: Pusapati
authors: Alexander
authors: A
authors: Kleger
authors: Peter
authors: P
authors: Möller
authors: Rainer
authors: R
authors: Küfer
authors: Felicitas
authors: F
authors: Genze
authors: Martin
authors: M
authors: Wagner
authors: Johan
authors: J
authors: van Lint
authors: Peter
authors: P
authors: Carmeliet
authors: Guido
authors: G
authors: Adler
authors: Thomas
authors: T
authors: Seufferlein
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000201:enzymology; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology; D005770:Gastrointestinal Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D000091283:Protein Kinase D2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases