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.
Aim 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.
Conclusion 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.
- protein kinase D2
- pancreatic cancer
- cell proliferation
- cell signalling
- gastric cancer
- pancreatic cancer
- Revised 6 May 2010
- Accepted 29 May 2010
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GVP and AK contributed equally.
Funding This project was funded in part by the German Federal Ministry of Education and Research (BMBF) grant no. PKB-01GS08209-4 to TS and by the DFG (SFB518 B3, to TS). The authors are responsible for the content of this paper. Work in the laboratory of JVL is supported by the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen (G.0612.07) and by the IAP programme of the Belgian Federal Government (IAP 6/18).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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