Z Gastroenterol 2009; 47 - V13
DOI: 10.1055/s-0029-1241230

Role of protein kinase D2 in pancreas tumor growth and tumor angiogenesis

N Azoitei 1, GV Pusapati 1, F Genze 2, G Adler 1, T Seufferlein 3
  • 1Universitätsklinikum Ulm, Zentrum für Innere Medizin I, Ulm, Germany
  • 2Universität Ulm, Urologie, Ulm, Germany
  • 3Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Innere Medizin I, Halle (Saale), Germany

Introduction: Growth of pancreatic carcinoma is thought to be highly dependent on angiogenesis, a process which drives the formation of new blood vessels from pre-existing capillaries or venules. Tumor progression towards an aggressive, metastatic state is associated with multiple genetic changes, including changes leading to increased production of angiogenic factors. However, the signaling pathways governing tumor angiogenesis are not yet clearly understood. The protein kinase D (PKD) family of serine/threonine kinases belongs to the subfamily of the calcium-calmodulin kinase-like superfamily that comprises of PKD1/protein kinase Cµ, PKD2, and PKD3/protein kinase Cv. PKD isoforms have been implicated in various biological processes, including cell proliferation, regulation of Golgi function and apoptosis.

Aim: The aim of this study was to investigate the implication of Protein kinase D isoforms in pancreas tumor growth and tumor angiogenesis.

Approach: In the present work the tumor angiogenesis was investigated in two in vivo models:

  • the chicken chorionallantoic membrane (CAM) assay and

  • human tumor xenograft on athymic mice.

Results: We were able to show that upon knocking-down of the PKD isoforms by using specific siRNA either on chicken CAM or in pancreas carcinoma cells, both the tumor growth and angiogenesis are dramatically impaired as demonstrated by immunohistological stainings with specific markers for proliferation (Ki67) and for endothelial cells (von Willibrand Factor and Desmin). A novel approach of targeting PKD2 in vivo using antisense Vivo-Morpholino oligonucleotides demonstrated that mice injected with PKD2-specific Morpholino developed significantly smaller tumors compared to control animals. The reduction in tumor size was associated with a marked reduction in Desmin, von Willebrand Factor and CD31 immunoreactivity both in vessels surrounding the tumor and within the tumor xenografts of mice treated with PKD2-MO.

Conclusion: Collectively, these finding demonstrate the role of PKD as a critical regulator of tumor angiogenesis and it could provide a useful target for regulation of pathological angiogenesis.