New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF.
Our analyses in several different tumor settings challenge the prevailing view that malignancies and metastases generally initiate as avascular masses that only belatedly induce vascular support. Instead, we find that malignant cells rapidly co-opt existing host vessels to form an initially well-vascularized tumor mass. Paradoxically, the co-opted vasculature does not undergo angiogenesis to support the growing tumor, but instead regresses (perhaps as part of a normal host defense mechanism) via a process that involves disruption of endothelial cell/smooth muscle cell interactions and endothelial cell apoptosis. This vessel regression in turn results in necrosis within the central part of the tumor. However, robust angiogenesis is initiated at the tumor margin, rescuing the surviving tumor and supporting further growth. The expression patterns of Angiopoietin-2 (the natural antagonist for the angiogenic Tie2 receptor) and vascular endothelial growth factor (VEGF) strongly implicate these factors in the above processes. Angiopoietin-2 is highly induced in co-opted vessels, prior to VEGF induction in the adjacent tumor cells, providing perhaps the earliest marker of tumor vasculature and apparently marking the co-opted vessels for regression. Subsequently, VEGF upregulation coincident with Angiopoietin-2 expression at the tumor periphery is associated with robust angiogenesis. Thus, in tumors, Angiopoietin-2 and VEGF seem to reprise the roles they play during vascular remodeling in normal tissues, acting to regulate the previously underappreciated balance between vascular regression and growth.
Holash
J
J
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York, NY 10591, USA.
Wiegand
S J
SJ
Yancopoulos
G D
GD
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D001808:Blood Vessels / Q000473:pathology / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000502:physiology; D006801:Humans; D008222:Lymphokines / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D011506:Proteins / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors