Tumor production of angiostatin is enhanced after exposure to TNF-alpha.
Infection of tumors with an adenoviral vector expressing a chimeric gene composed of the CArG elements of the Egr-1 promoter and a cDNA encoding TNF-alpha (Ad.Egr-TNF) has previously been shown to result in the production of high intratumoral levels of TNF-alpha and thereby tumor regression. The antitumor effects of TNF-alpha were ascribed to vascular thrombosis. We and others, have reported that inhibition of tumor vessel thrombosis using anticoagulation therapy does not abrogate the antitumor effects after TNF-alpha treatment. To investigate the potential antiangiogenic effects of TNF-alpha, we studied the generation of angiostatin after intratumoral injection of Ad.Egr-TNF. We report an increase in plasma angiostatin levels both during and after treatment with Ad.Egr-TNF that parallel tumor regression. We also report that TNF-alpha enhances angiostatin production by inducing the activity of plasminogen activator and the release of MMP-9 by tumor cells. These studies support a model in which the antiangiogenic effects of TNF-alpha on the tumor microvasculature are mediated by generation of angiostatin.
Mauceri
Helena J
HJ
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
Seetharam
Saraswathy
S
Beckett
Michael A
MA
Lee
John Y
JY
Gupta
Vinay K
VK
Gately
Stephen
S
Stack
M Sharon
MS
Brown
Charles K
CK
Swedberg
Kirsten
K
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D043168:Angiostatins; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000098:blood supply* / Q000628:therapy; D017077:Culture Media, Conditioned / Q000737:chemistry; D003673:Defective Viruses / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000097:blood; D010958:Plasminogen / Q000096:biosynthesis* / Q000378:metabolism*; D010960:Plasminogen Activators / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000378:metabolism / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D017077:Culture Media, Conditioned; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D043168:Angiostatins; D010958:Plasminogen; D010960:Plasminogen Activators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9