Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation.
Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after treatment cessation. To assess the responses to irradiation and vascular endothelial growth factor-receptor tyrosine kinase inhibition (by the vascular endothelial growth factor tyrosine kinase inhibitor PTK787/ZK222854), mammary carcinoma allografts were investigated by vascular casting; electron, light, and confocal microscopy; and immunoblotting. Irradiation and anti-angiogenic therapy had similar effects on the tumor vasculature. Both treatments reduced tumor vascularization, particularly in the tumor medulla. After cessation of therapy, the tumor vasculature expanded predominantly by intussusception with a plexus composed of enlarged sinusoidal-like vessels containing multiple transluminal tissue pillars. Tumor revascularization originated from preserved alpha-smooth muscle actin-positive vessels in the tumor cortex. Quantification revealed that recovery was characterized by an angiogenic switch from sprouting to intussusception. Up-regulated alpha-smooth muscle actin-expression during recovery reflected the recruitment of alpha-smooth muscle actin-positive cells for intussusception as part of the angio-adaptive mechanism. Tumor recovery was associated with a dramatic decrease (by 30% to 40%) in the intratumoral microvascular density, probably as a result of intussusceptive pruning and, surprisingly, with only a minimal reduction of the total microvascular (exchange) area. Therefore, the vascular supply to the tumor was not severely compromised, as demonstrated by hypoxia-inducible factor-1alpha expression. Both irradiation and anti-angiogenic therapy cause a switch from sprouting to intussusceptive angiogenesis, representing an escape mechanism and accounting for the development of resistance, as well as rapid recovery, after cessation of therapy.
Hlushchuk
Ruslan
R
Institute of Anatomy, University of Bern, Bern, Switzerland.
Riesterer
Oliver
O
Baum
Oliver
O
Wood
Jeanette
J
Gruber
Guenther
G
Pruschy
Martin
M
Djonov
Valentin
V
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000628:therapy* / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000532:radiotherapy*; D010793:Phthalazines / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011725:Pyridines / Q000627:therapeutic use*; D011839:Radiation, Ionizing; D013997:Time Factors; D014022:Tissue Survival / Q000187:drug effects / Q000528:radiation effects; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
D000199:Actins; D000970:Antineoplastic Agents; D010793:Phthalazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011725:Pyridines; C404768:vatalanib
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