Influence of TBK-1 on tumor angiogenesis and microvascular inflammation.
Tank-Binding-Kinase 1 (TBK-1) has been proposed as a putative mediator in tumor angiogenesis. It was the aim of our study to gain insight into TBK-1s role in tumor angiogenesis and tumor-associated microvascular inflammation. TBK-1 overexpressing KB 3-1 cells were generated and their growth characteristics were analyzed. Expression of TBK-1, VEGF, RANTES and Il-8 were quantified using qPCR and western blot analysis. Intravital microscopy using the dorsal skinfold chamber model in nude mice addressed total (TIVD) and functional intratumoral vascular density (FIVD), perfusion index, vessel diameter and leukocyte sticking. Transfection of KB-3 cells resulted in significantly increased TBK-1, RANTES and IL-8 expression without affecting cellular growth. Supernatants from TBK-1 overexpressing clones induced HUVEC proliferation. Intravital microscopy identified an increase in leukocyte sticking paralleled by significantly increased TIVD and FIVD as a result of increased VEGF expression. Therefore, TBK-1 represents a novel mediator of tumor angiogenesis and exerts proinflammatory effects via upregulation of inflammatory cytokines. The TBK-1 pathway might be an important cross-link between angiogenesis and inflammation representing a possible target for anti-tumor therapy.
Department of Neurosurgery, Charite Universitaetsmedizin, Berlin, Germany. marcus.czabanka@charite.de
Marcus
M
Czabanka
Christian
C
Korherr
Ulrich
U
Brinkmann
Peter
P
Vajkoczy
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018946:Chemokine CCL5 / Q000502:physiology; D002999:Clone Cells; D006801:Humans; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control; D016209:Interleukin-8 / Q000502:physiology; D007624:KB Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000473:pathology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D009389:Neovascularization, Pathologic; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D000970:Antineoplastic Agents; D018946:Chemokine CCL5; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human