Z Gastroenterol 2010; 48 - V41
DOI: 10.1055/s-0030-1263395

Role of Protein kinase D2 in pancreatic tumor growth and tumor angiogenesis

N Azoitei 1, GV Pusapati 1, A Kleger 1, C Brunner 2, F Genze 2, C Ruhland 1, G Adler 1, T Seufferlein 1, 3
  • 1Uniklinikum Ulm, Ulm, Germany
  • 2Universität Ulm, Ulm, Germany
  • 3Uniklinikum Halle/Saale, Halle, Germany

Introduction: 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. We found PKD2 to be highly expressed in pancreatic cancer as well as in the tumor associated endothelia.

Aim: The aim of this study was to investigate the role of Protein kinase D2 in pancreatic tumor growth and tumor angiogenesis.

Approach: The role of PKD2 in tumor angiogenesis was investigated in two in vivo models of human tumor xenografts in athymic mice (1. orthotopic and 2. subcutaneous).

Results: Depletion of PKD2 in human pancreatic cancer cells upon stable expression of a GFP-miR that specifically targets this kinase (GFP-miR-PKD2) followed by orthotopic implantation to mouse pancreas resulted in a significantly decreased tumor growth compared to tumors expressing a scrambled GFP-miR. Examination of peritumoral blood vessel formation in tumors expressing GFP-miR-PKD2 revealed a marked reduction in Desmin, von Willebrand Factor, CD31 and CD34 immunoreactivity within and around the tumors compared to tumors expressing the scrambled GFP-miR. Concomitantly, the marked reduction in angiogenesis was accompanied by a significant decrease in the number of Ki67-positive tumor cells. A novel approach of targeting PKD2 in vivo using antisense Vivo-Morpholino oligonucleotides applied i.v. demonstrated that mice injected with a Morpholino that specifically targets murine PKD2, 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 that PKD2 is a critical regulator of tumor angiogenesis and a novel therapeutic target.