Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2.
Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in tumour cells but no Ang-2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang-2 in the tumour vasculature, whereas no Ang-1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within tumours.
Reiss
Yvonne
Y
Institute of Neurology/Edinger Institute, Frankfurt University Medical School, Frankfurt, Germany.
Knedla
Anette
A
Tal
Andrea O
AO
Schmidt
M H H
MHH
Jugold
Manfred
M
Kiessling
Fabian
F
Burger
Angelika M
AM
Wolburg
Hartwig
H
Deutsch
Urban
U
Plate
Karl H
KH
D042683:Angiopoietin-1 / Q000032:analysis / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D020286:Pericytes / Q000473:pathology; D010641:Phenotype; D042787:Receptor, TIE-2 / Q000378:metabolism; D014183:Transplantation, Heterologous
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042787:Receptor, TIE-2