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Radiation-induced Increase in Invasive Potential of Human Pancreatic Cancer Cells and Its Blockade by a Matrix Metalloproteinase Inhibitor, CGS27023

Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 [L-W. Q., K. M., T. U., E. N., N. M., N. S., M. T.] and Research Division, Novartis Tsukuba Research Institute, Okubo 8, Tsukuba 300-2611, Japan [M. N.]

Purpose: Radiotherapy remains a major therapeutic option for patients with advanced pancreatic cancer. Nevertheless, the effects of irradiation on malignant biological behaviors (e.g., migration and invasion of cancer cells) have yet to be clarified. Thus, we conducted an in vitro study to investigate the radiation-induced alterations around cell migration and invasion capacity.

Experiment design: Three cell lines from human pancreatic cancer were included in the study. -radiation was used for irradiation treatment. Cell migration and invasion ability were evaluated by Transwell migration assay and Matrigel invasion assay. The activity of MMP-2 and 9, and expression of urokinase-type plasminogen activator were investigated with gelatin zymography and immunoblot, respectively.

Results: Irradiation enhances invasive potential in some pancreatic cancer cells, whereas it significantly inhibits cell proliferation and migration. This hitherto unknown biological effect of irradiation involves enhanced matrix metalloproteinase (MMP)-2 activity. Consequently, simultaneous administration of an MMP inhibitor, CGS27023A, suppresses the radiation-enhanced invasion through blockade of transition of MMP-2 from latent type to active type.

Conclusion: Because radiation may increase invasion ability through activating MMP proteolytic system, simultaneous administration of the MMP inhibitor during radiotherapy could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for pancreatic cancer.

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