Inhibitory effect of a serine protease inhibitor, FOY-305 on the invasion and metastasis of human pancreatic cancers

Ohta, Tetsuo; Futagami, Fumio; Tajima, Hidehiro; Kitagawa, Hirohisa; Kayahara, Masato; Nagakawa, Takukazu; Miwa, Koichi; Yamamoto, Miyuki; Iseki, Shoichi; Nakanuma, Yasuni; Terada, T

doi:10.3892/ijo.11.4.813

Cited by 8 publications

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“…2). The levels of trypsinogen mRNA in the transfectants were almost the same as that in Capan-1 cells, which retain invasion properties similar to those observed in pancreatic tumors in vivo 25 (Fig. 2).…”

Section: Establishment Of Cell Lines Stably Transfected With Trypsinosupporting

confidence: 56%

“…20,21 In previous studies, we demonstrated in pancreatic cancer cell lines that hepatic metastasis and invasive ability were correlated with amounts of cationic trypsinogen and were inhibited by a serine protease inhibitor. 24,25 Considering the results of this earlier work, secreted cationic trypsin is likely to degrade extracellular matrix components in several ways, including activating trypsinogen itself as well as latent proenzyme forms of other proteases. Notably, Panc-1 cells express u-PA and MMP-2 (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…24 Furthermore, we found that serine protease inhibitors had a suppressive effect on invasion and metastasis by human pancreatic cancer cell lines. 25 However, the importance of trypsin in initiating invasion of tumor cells is still unclear; 1 major reason is that no available serine protease inhibitor can produce sufficiently selective inhibition of trypsin.To obtain more direct evidence that trypsin potentiates tumor invasion, we transfected cationic trypsinogen cDNA into Panc-1, a pancreatic adenocarcinoma-derived cell line that normally is deficient in expression of trypsinogen. The resulting transfectants acquired enhanced invasiveness.…”

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Enhanced invasiveness of pancreatic adenocarcinoma cells stably transfected with cationic trypsinogen cDNA

et al. 2001

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Various studies have described increased expression of cationic trypsinogen in malignant tumor cells. To explore the role of secreted cationic trypsinogen in invasion by cancer cells, we introduced cationic trypsinogen cDNA into Panc-1, a pancreatic adenocarcinoma-derived cell line that lacks expression of endogeneous trypsinogen. Four independent clones (designated Panc-1-Try-7, -9, -11 and -24) stably expressing cationic trypsinogen mRNA were isolated and processed for further study. In a zymographic analysis, gelatinolytic activity for cationic trypsinogen was detectable in serum-free conditioned media obtained from all 4 transfectants but not in media from mock-transfected or parental Proteolytic degradation of extracellular matrix components is a process essential for tumor invasion and metastasis. 1-4 A variety of proteases produced by tumor cells are involved in matrix degradation. 1-4 These enzymes include 2 major categories: matrix metalloproteinases (MMPs) and serine proteases. Although the role of MMPs in tumor malignancy has been studied extensively, 5-9 much less is known about serine proteases, except for urokinase-type plasminogen activator (u-PA). 10 -13 Although trypsin, another member of the serine protease family, also has been implicated in the spread of malignant tumor cells, the underlying molecular mechanism has not been fully elucidated. Several previous reports have described increased amounts of trypsinogen-like enzymes in malignant tumor cells. 14 -21 Koshikawa et al. 22 identified 1-and 2-chain forms of cationic trypsinogen in a gastric carcinoma cell line. Under the acidic condition that prevails in the extracellular space between malignant tumor cells, cationic trypsinogen is spontaneously converted to trypsin, an active form. 23 Trypsin not only degrades extracellular matrix glycoproteins 22 but also activates proenzymes of various MMP and serine proteases. 19 We previously reported that under acidic conditions cationic trypsinogen produced by human pancreatic ductal cancer spontaneously becomes activated and acquires gelatinolytic activity. 24 Furthermore, we found that serine protease inhibitors had a suppressive effect on invasion and metastasis by human pancreatic cancer cell lines. 25 However, the importance of trypsin in initiating invasion of tumor cells is still unclear; 1 major reason is that no available serine protease inhibitor can produce sufficiently selective inhibition of trypsin.To obtain more direct evidence that trypsin potentiates tumor invasion, we transfected cationic trypsinogen cDNA into Panc-1, a pancreatic adenocarcinoma-derived cell line that normally is deficient in expression of trypsinogen. The resulting transfectants acquired enhanced invasiveness. MATERIAL AND METHODS Cell cultureHuman pancreatic adenocarcinoma cell lines, (Capan-1, BxPC-3, AsPC-1, Panc-1 and MIAPaCa-2), were obtained from the American Type Culture Collection (Rockville, MD). These cell lines were maintained at 37°C in a 5% CO 2 incubator and grown in RPMI-1640 medium supplemented w...

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Section: Establishment Of Cell Lines Stably Transfected With Trypsinosupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Enhanced invasiveness of pancreatic adenocarcinoma cells stably transfected with cationic trypsinogen cDNA

et al. 2001

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“…However, liver metastases are consistently generated only with certain cell lines of the pancreas, colon, and stomach that have a high metastatic potential to liver (4)(5)(6)(7)(8). Moreover, many cell lines do not generate consistent liver metastases when administered as single cell suspensions (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Consistent Liver Metastases in a Rat Model by Portal Injection of Microencapsulated Cancer Cells

Enomoto¹,

Oda²,

Aoyagi³

et al. 2006

Cancer Research

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Consistent liver metastases in animal models is generally observed only with certain cancer cell lines. With the aim of improving on existing animal models of liver metastases, we hypothesized that cancer cells encased in 300 Mm microcapsules, mimicking micrometastatic foci, might be effective seeds of liver metastases. A total of 3,000 microcapsules, containing 700 to 1,500 viable cells/capsule in logarithmic growth phase of three human pancreatic cancer cell lines (SUIT-2, AsPC-1, and BxPC-3), were transplanted in nude rats by portal injection. The rate of liver metastases was 100% (12 of 12), 100% (6 of 6), and 83% (5 of 6) for SUIT-2, AsPC-1, and BxPC-3 microcapsules, respectively. In contrast, the administration of an identical number of single cancer cells (2.1-4.5 Â 10 6 ) did not lead to liver metastases. Metastases was strictly limited to the liver, was quite stable, and could be proportionately tailored by varying the number of cancer microcapsules administered. Microscopic observation showed that two-thirds of the cancer microcapsules were lodged in the peripheral small (20-50 Mm) portal veins, although onethird of the cancer microcapsules were trapped in the central wide (200-400 Mm) portal vein. Capsules began to burst at day 3, with recognizable metastases produced at day 7, resulting in overt metastases production at days 28 to 42. The present cancer microcapsule method may be useful for obtaining liver metastases in animal models, especially for cell lines that will not form liver metastases with conventional single cell injection methods and/or for experiments requiring the consistent formation of liver metastases. (Cancer Res 2006; 66(23): 11131-9)

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Expression of protease activated receptor-2 (PAR-2) in gastric cancer

et al. 2006

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Inhibitory effect of a serine protease inhibitor, FOY-305 on the invasion and metastasis of human pancreatic cancers

Cited by 8 publications

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Enhanced invasiveness of pancreatic adenocarcinoma cells stably transfected with cationic trypsinogen cDNA

Enhanced invasiveness of pancreatic adenocarcinoma cells stably transfected with cationic trypsinogen cDNA

Consistent Liver Metastases in a Rat Model by Portal Injection of Microencapsulated Cancer Cells

Expression of protease activated receptor-2 (PAR-2) in gastric cancer

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