Vascular integration of endothelial progenitors during multistep tumor progression.
Bone marrow-derived endothelial precursor cells contribute to tumor neovascularization. However, it is unclear when during progressive tumor growth circulating precursors are recruited into the preexisting vascular network, and how they home specifically into the tumor microenvironment. Here, we summarize recent findings from mouse models of multistage carcinogenesis, which reveal distinct phases of angiogenic activity. Only advanced tumors with a highly heterogeneous, sprouting vasculature recruite endothelial progenitors into neovessels. Surprisingly, during progressive tumor growth endothelial cells acquire new characteristics and secrete CC chemokines, a group of chemoattractants with adjacent cysteins, which play a dual role by enhancing neovascularization in an autocrine and endocrine fashion. Locally, chemokines stimulate endothelial proliferation; systemically, they guide chemokine receptor-positive circulating progenitors into the tumor bed. Subsequently, endothelial progenitors are truly integrated into the network of pre-existing vessels. This mechanism represents a novel concept where not the tumor itself, but endothelial cells as components of the tumor-induced stroma foster neovascularization in a self-amplifying loop.
Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
Günter J
GJ
Hämmerling
Ruth
R
Ganss
D000818:Animals; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D013234:Stem Cells / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A