Inhibition of invasion, angiogenesis, tumor growth, and metastasis by adenovirus-mediated transfer of antisense uPAR and MMP-9 in non–small cell lung cancer cells
- 1 September 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 4 (9), 1399-1408
- https://doi.org/10.1158/1535-7163.mct-05-0082
Abstract
Lung cancer is currently the leading cause of cancer deaths in the United States. Conventional therapeutic treatments, including surgery, chemotherapy, and radiation therapy, have achieved only limited success. The overexpression of proteases, such as urokinase-type plasminogen activator (uPA), its receptor (uPAR), and matrix metalloproteinases (MMP), is correlated with the progression of lung cancer. In the present study, we used a replication-deficient adenovirus capable of expressing antisense uPAR and antisense MMP-9 transcripts to simultaneously down-regulate uPAR and MMP-9 in H1299 cells. Ad-uPAR-MMP-9 infection of H1299 cells resulted in a dose- and time-dependent decrease of uPAR protein levels and MMP-9 activity as determined by Western blotting and gelatin zymography, respectively. Corresponding immunohistochemical analysis also showed that Ad-uPAR-MMP-9 infection inhibited uPAR and MMP-9 expression. As shown by Boyden chamber assay, Ad-uPAR-MMP-9 infection significantly decreased the invasive capacity of H1299 cells compared with mock and Ad-CMV (empty vector)–infected cells in vitro. Furthermore, Ad-uPAR-MMP-9 infection inhibited capillary-like structure formation in H1299 cells cocultured with endothelial cells in a dose-dependent manner compared with mock- and Ad-CMV-infected cells. Ad-uPAR-MMP-9 injection caused the regression of s.c. induced tumors after s.c. injection with H1299 lung cancer cells and inhibited lung metastasis in the metastatic model with A549 cells. These data suggest that Ad-uPAR-MMP-9 shows its antitumor activity against both established and early phases of lung cancer metastases by causing the destruction of the tumor vasculature. In summary, adenovirus-mediated inhibition of uPA-uPAR interaction and MMP-9 on the cell surface may be a promising anti-invasion and antimetastatic strategy for cancer gene therapy.Keywords
This publication has 64 references indexed in Scilit:
- A Protective Role for Matrix Metalloproteinase-3 in Squamous Cell CarcinomaCancer Research, 2004
- A third‐generation matrix metalloproteinase (MMP) inhibitor (ONO‐4817) combined with docetaxel suppresses progression of lung micrometastasis of MMP‐expressing tumor cells in nude miceInternational Journal of Cancer, 2002
- Prognostic impact of matrix metalloproteinase‐9 in operable non‐small cell lung cancerInternational Journal of Cancer, 2002
- Matrix Metalloproteinase Inhibitors and Cancer—Trials and TribulationsScience, 2002
- Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in miceGene Therapy, 1998
- Regulation of Integrin Function by the Urokinase ReceptorScience, 1996
- Cooperative effect of TNFalpha, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity.The Journal of cell biology, 1996
- Blockage of urokinase receptor reduces in vitro the motility and the deformability of endothelial cellsFEBS Letters, 1996
- Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinomaCell, 1994
- Expression of collagenase‐related metalloproteinase genes in human lung or head and neck tumoursInternational Journal of Cancer, 1991