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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.]

	ABSTRACT

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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.

	INTRODUCTION

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Pancreatic cancer is one of the most aggressive and lethal neoplasms with an extremely low 5-year survival rate (1 , 2) .

Because most patients with this disease miss the opportunity for complete surgical resection at the time of diagnosis, radiotherapy remains as a major component of treatment modalities for controlling tumor progression. However, pancreatic cancer often shows resistance to radiation (3) . The precise mechanism underlying this radio-resistance remains unknown, but several factors have been reported to be involved including cell types, degree of differentiations (4) , cell cycle (5) , DNA ploidy (6) , p53/p21 status (7) , and DNA-dependent protein kinase activity (8) .

Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on other biological behaviors including motility, invasiveness, and metastatic potential. In this respect, conventional colony formation assay or cell viability assay may be insufficient to evaluate the therapeutic effect of radiotherapy. Changes in motility or invasive potential after irradiation have been poorly understood.

In the present study, we examined the effects of irradiation on proliferation, motility, and invasiveness of pancreatic cancer cells. On the basis of the finding of enhancement of invasive potential by irradiation in a subset of pancreatic cancer cells, we expanded the investigations into two proteolytic systems known as crucially relevant to tumor invasive phenotypes, the uPA² and MMPs. Because the increased expression/activity of MMP-2 was shown as a causative event of the enhanced invasion, a synthetic MMP inhibitor was used to block the radiation-induced increase in invasive potential. Thus, we try to provide evidence that the concomitant use of MMP inhibitors during radiotherapy could be a potential therapeutic approach to improve the efficacy of radiotherapy for pancreatic cancer.

	MATERIALS AND METHODS

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Cell Culture and Reagents.
Three human pancreatic cancer cell lines were used in this study. Panc-1 and Suit-2 were generously provided by Dr. H. Iguchi (National Kyushu Cancer Center, Fukuoka, Japan), Hs766T was obtained from American Type Culture Collection (Rockville, MD). Cells were maintained in DMEM (Sigma Chemical Co., St. Louis, MO) supplemented with 10% fetal bovine serum, streptomycin (100 µg/ml), and penicillin (100 units/ml) at 37°C with humidified 90% air and 10% CO_2. The number of cells was counted with a particle distribution counter, CDA500 (Sysmex, Kobe, Japan). The MMP inhibitor CGS27023A was kindly provided by Novartis Pharma, Inc., Tsukuba, Japan.

Irradiation.
The cells were irradiated with doses of 3, 5, or 10 Gy at room temperature using a ¹³⁷Cs source (Gamma Cell 40; Atomic Energy of Canada Ltd., Ontario, Canada) delivering 1 Gy/min.

Cell Proliferation Assay.
Cell proliferation was evaluated by measuring the fluorescence intensity of PI as described previously with minor modifications (9) . Briefly, cells were seeded in 24-well plates at a density of 3 x 10⁴ cells/well. After overnight cultivation, cells were irradiated and cultured for 4 days. PI (30 µM) and digitonin (600 µM) were added to each well to label all nuclei of the cells with PI. Fluorescence intensity corresponding to total cells in each well was measured by a multiwell plate-reader, CYTOFLUOR II (PerSeptive Biosystems Inc., Framingham, MA) with 530-nm excitation and 645-nm emission filters. The cell proliferation rate was calculated as the proportion of fluorescence intensity of each well at the time point indicated in the text to that at the day of irradiation.

Migration Assay.
Migration of pancreatic cancer cells through 8-µM pores was assessed using the Transwell cell culture chamber (6.5-mm diameter; Corning Costar, Tokyo, Japan) as described in detail in our previous publications (10 , 11) . Cells at a density of 1 x 10⁴ were seeded in the upper chambers with 100 µl of medium supplemented with 10% fetal bovine serum. Same medium of 600 µl were placed in the lower wells. After seeding, the cells were subjected to irradiation and then cultured for 24 h. The filter membranes were removed and fixed with 70% ethanol and stained with H&E. The number of cells that had migrated to the lower surface of the filter membrane was counted in five random fields under a light microscope.

Matrigel Invasion Assay.
Invasion of pancreatic cancer cells was measured by the invasion of cells through Matrigel-coated transwell inserts (Becton Dickinson, Franklin Lakes, NJ) as reported previously (10 , 11) . Briefly, transwell inserts with 8-µm pores were coated with Matrigel (40 µg/well; Becton Dickinson, Bedford, MA). Cell suspension (500 µl; 1 x 10⁵/ml) was added to the upper chambers. Same medium of 750 µl were placed in the lower wells. Thereafter, the cells were irradiated and incubated for 24 h. Cells that had invaded to lower surface of the Matrigel-coated membrane were fixed with 70% ethanol, stained with H&E, and counted in five random fields under a light microscope.

Gelatin Zymography.
The conditioned medium either from nonirradiated or irradiated Panc-1 cells was concentrated to 10-fold with Centricon-10 (Amico, Beverly, MA). Samples were added to each lane and subjected to 10% SDS-PAGE using 10% polyacrylamide gel containing 1 mg/ml gelatin. After electrophoresis, the gel was washed in 2.5% Triton X-100, and incubated in 50 mM Tris-HCl buffer (pH 8.0) containing 0.5 mM CaCl₂ and 1 mM ZnCl₂ for 20 h at 37°C. The gel was stained with 1% Coomassie Brilliant Blue R-250 and destained with destaining buffer (5% acetic acid and 10% methanol).

Western Blotting.
The proteins (80 µg/lane) from the soluble fraction of Panc-1 cells were fractionated by 10% SDS-PAGE and transferred to a polyvinylidene difluoride membrane (Millipore, Bedford, MA). The membrane was incubated with 1:500 dilutions of polyclonal antibody for human uPA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with antigoat IgG conjugated with horseradish peroxides (Santa Cruz Biotechnology). Immunoblots were detected by the enhanced chemiluminescence (Amersham International, Buckinghamshire, United Kingdom).

Statistical Analysis.
Statistical analyses were performed by using ANOVA and unpaired Student’s t test. All of the statistics were performed on two-sided test. P < 0.05 was considered as significant. Each experiment was repeated at least three times.

	RESULTS

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Irradiation Inhibits Proliferation of Pancreatic Cancer Cells.
First, we examined the proliferation of pancreatic cancer cells after irradiation. Irradiation suppressed the proliferation of Panc-1 cells in a dose-dependent manner, and an almost complete inhibition was observed at a dose of 10 Gy (Fig. 1) . Similar results were obtained in Suit-2 at the same dose range. However, in Hs766T cells whereas dose reached to 5 Gy, radiation had already entirely inhibited the cell growth (data not shown).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Irradiation inhibits the growth of pancreatic cancer cells in a dose-dependent manner. Panc-1 cells were irradiated with 3 Gy (), 5 Gy (), or 10 Gy (•), and the relative proliferation rates were determined at 1, 2, 3, and 4 days after irradiation; bars, ± SD.

View this table: [in this window] [in a new window]   Table 2 Results of Matrigel invasion assay in three pancreatic cancer cell lines under graded doses of irradiationa

View larger version (58K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Irradiation promotes the invasiveness of cultured pancreatic cancer cells. A, representative pictures of Matrigel invasion assay show an increase in the number of invading Panc-1 cells after irradiation (power of 200-fold; H&E stain). B, irradiation promotes the invasiveness of pancreatic cancer cells in a dose-dependent manner. Panc-1 cells were irradiated with 0 (control), 3, 5, and 10 Gy, and subjected to Matrigel invasion assay after 24 h. There are significant differences in the numbers of invading cells after irradiation at any doses comparing with untreated control (P < 0.01); bars, ± SD.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Irradiation increases MMP-2 activity in pancreatic cancer cells. Gelatin zymography of irradiated Panc-1 cells shows increased activities in both latent type (Mr 72,000) and active type (Mr 62,000) of MMP-2, compared with untreated control.

View larger version (78K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. The MMP inhibitor, CGS27023A, blocks the radiation-enhanced invasiveness in Panc-1 cells. A, representative pictures of invasion assay show that CGS27023A blocks the increase in invading cells induced by irradiation (power of 50-fold; H&E stain). B, CGS27023A significantly suppresses the number of invading cells after irradiation when treated at concentrations of 5 µM and 10 µM (P < 0.001, compared with untreated control). CGS27023A also significantly suppresses the number of invading cells without irradiation when treated at concentrations of 5 µM and 10 µM (P < 0.01, compared with untreated control). Panc-1 cells were unirradiated () or irradiated with 5 Gy (•), in combination with CGS27023A at 0, 1, 5, and 10 µM, and subjected to invasion assay after 24 h; bars, ± SD.

View larger version (41K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Gelatin zymography of Panc-1 cells after irradiation with 5 Gy (or 0 Gy; control) shows treatment with CGS27023A (5 µM) results in an almost complete obliteration of active type of MMP-2. There is no significant change in activities of latent type MMP-2.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Fig. 6. Irradiation suppresses the constituent uPA expressions in Panc-1 cells. After 24 h of irradiation, lysates from Panc-1 cells were measured for the expression of uPA by Western blotting. Actin serves as a control.

	DISCUSSION

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Importantly, radiation-induced enhancement in invasiveness was observed at doses used clinically as a fractionated irradiation for pancreatic carcinoma. This implies that the feasibility of the current radiotherapy needs to be reconsidered. Recently, similar findings were reported by other investigators. Wild-Bode et al. (12) showed that sublethal doses of irradiation enhanced the migration and invasiveness of human glioblastoma cells in association with enhanced expression/activity of MMP-2 and MMP-9. Furthermore, Camphausen et al. (13) reported that radiation therapy to a primary Lewis lung carcinoma accelerated metastatic growth in mice. These findings support our present results in pancreatic cancer cells. Notably, however, of three lines of pancreatic cancer cells studied, there is one line (Hs766T) displaying no response to irradiation in regard to cell migration or invasion statues. Additional investigations are needed for elucidating the relevant molecular mechanisms behind the different responses toward irradiation.

We found that the increased invasiveness after irradiation was associated with increased expression and activity of MMP-2. Previous reports also described the increased expression of MMP-2 after irradiation (12 , 14) . MMP-2 has two types, latent type and active type. Through a complex series of biochemical interactions, M_r 72,000 of latent MMP-2 is cleaved to form M_r 62,000 active type (15) . Consistent with our present results, several studies have shown that synthetic MMP inhibitors block the invasion and metastasis of pancreatic cancer cells by inhibiting MMP activation process from latent type to active type (16 , 17) .

The present study demonstrated that irradiation suppressed the motility in some pancreatic cancer cells. It has been suggested that uPA and its uPA receptor may play a key role in the regulation of cell motility as well as proteolysis (18 , 19) . Carriero et al. (20) reported that the ligation between uPA and uPA receptor initiated remarkable cytoskeletal rearrangements and promoted cell migration in breast cancer. After irradiation, uPA expression was reduced in association with a decreased motility. Thus, we suggest that the decreased motility after irradiation may account, at least in part, for the decreased expression of uPA.

We also demonstrated that a synthetic MMP inhibitor, CGS27023A, blocked the activation of MMP-2 and, subsequently, radiation-enhanced invasiveness. Several MMP inhibitors have been developed, and some of them have already been evaluated in clinical trials for treatment of aggressive tumors including pancreatic cancer (21) . MMP inhibitors inherently do not cause leucopoenia, a universal side effect of conventional anticancer agents. In the present study, CGS27023A showed no effect on cell viability and proliferation. CGS27023A is a potent inhibitor of several MMPs including collagenase, gelatinase, and stromelysin, and, importantly, this drug can be administered p.o. We believe that concomitant administration of CGS27023A during radiotherapy could be a novel approach to enhance the efficacy of radiotherapy for pancreatic cancer.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Phone: 81-92-642–5444; Fax: 81-92-642-5458; E-mail: mizumoto{at}mailserver.med.kyushu-u.ac.jp

² The abbreviations used are: uPA, urokinase-type plasminogen activator; MMP, matrix metalloproteinase; CGS27023A, N-hydroxy-2(R)-[[4-methoxysulfonyl](3-picolyl) amino]-3-methyl-butaneamide hydrochloride monohydrate; PI, propidium iodide.

Received 10/19/01; revised 12/28/01; accepted 1/ 7/02.

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