Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion.

Details

Serval ID
serval:BIB_A64704746F6A
Type
Article: article from journal or magazin.
Collection
Publications
Title
Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion.
Journal
Molecular Cancer Therapeutics
Author(s)
Kaliski A., Maggiorella L., Cengel K.A., Mathe D., Rouffiac V., Opolon P., Lassau N., Bourhis J., Deutsch E.
ISSN
1535-7163 (Print)
ISSN-L
1535-7163
Publication state
Published
Issued date
2005
Peer-reviewed
Oui
Volume
4
Number
11
Pages
1717-1728
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
In this study, we have evaluated the interactions between ionizing radiation and a matrix metalloproteinase (MMP) inhibitor. Using Matrigel invasion assays, we show that ionizing radiation induced a dose-dependent increase in the invasive phenotype of cultured B16 melanoma cells and that conditioned medium from these irradiated B16 cells promoted endothelial cell [human microvascular endothelial cells (HMEC)] invasiveness. To determine whether the radiation-induced changes in invasive phenotype could be due to changes in MMP activation, we have tested the ability of the MMP inhibitor Metastat to modulate the ionizing radiation-induced invasive phenotype using both an in vitro melanoma model and a mouse s.c. tumor model. In these studies, Metastat inhibited the ionizing radiation-induced invasive phenotype in cultured B16 cells and similarly inhibited the increase in HMEC invasion induced by conditioned medium from irradiated B16 cells. Conversely, ionizing radiation increased B16 MMP-2 activity and the conditioned medium from irradiated B16 induced HMEC MMP-2 activity. To further investigate the interaction between ionizing radiation and MMP activation, we then studied the effects of ionizing radiation on downstream effectors of the MMP system. We found that ionizing radiation induced vascular endothelial growth factor (VEGF) secretion by B16 melanoma cells and that this secretion was inhibited by Metastat. Similarly, conditioned medium from irradiated B16 was also able to increase VEGF secretion in HMECs. Moreover, ionizing radiation-induced melanoma cell invasiveness was partially inhibited by an anti-VEGF monoclonal antibody. In vivo, ionizing radiation plus concomitant Metastat yielded the greatest growth inhibition of melanoma s.c. tumors and this effect correlated with inhibition of angiogenesis as measured by both Doppler ultrasonography and platelet/endothelial cell adhesion molecule-1 staining. Finally, ionizing radiation modulated MMP-2, VEGF, and VEGF receptor expression in these tumor samples using immunohistochemistry. Taken together, these results suggest that there is an ionizing radiation-induced tumor survival pathway and a possible paracrine ionizing radiation-induced stimulatory pathway emanating from tumor cells toward the endothelial bed that is impeded when Metastat is given simultaneously. This model could provide in vivo evidence of the antitumor efficacy of combining a MMP inhibitor with ionizing radiation to target radiation-induced invasion and angiogenesis.
Keywords
Animals, Antibodies, Monoclonal/chemistry, Antigens, CD31/biosynthesis, Antineoplastic Agents/pharmacology, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cells, Cultured, Collagen/chemistry, Collagen/pharmacology, Culture Media, Conditioned/pharmacology, Dose-Response Relationship, Radiation, Drug Combinations, Endothelium, Vascular/pathology, Enzyme Inhibitors/pharmacology, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Laminin/chemistry, Laminin/pharmacology, Matrix Metalloproteinase 2/metabolism, Matrix Metalloproteinase 9/metabolism, Matrix Metalloproteinase Inhibitors, Melanoma, Experimental/drug therapy, Mice, Neoplasm Invasiveness, Neoplasm Transplantation, Neoplasms, Radiation-Induced/pathology, Neovascularization, Pathologic, Phenotype, Proteoglycans/chemistry, Proteoglycans/pharmacology, Radiation, Ionizing, Time Factors, Ultrasonography, Ultrasonography, Doppler, Vascular Endothelial Growth Factor A/immunology, Vascular Endothelial Growth Factor A/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
01/12/2014 17:42
Last modification date
20/08/2019 15:11
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