Acinar cell proliferation leads to Acinar cell tumors

Trypsin inhibitor-induced pancreatic tumor formation

Ingestion of raw soya flour, which contains trypsin inhibitory activity, by rats for 2 years induced pancreatic hypertrophy due to acinar cell hyperplasia and acinar cell tumors [Rackis JJ et al, 1985; Woutersen RA et al, 1991]. Rats given raw soya flour or the trypsin inhibitor camostat exhibited pancreatic hypertrophy and acinar cell hyperplasia, and rats administered the pancreatic carcinogen azaserine followed by camostat exhibited acinar cell tumor formation [Gumbmann MR et al, 1986; Lhoste EF et al, 1988; Bell RH Jr et al, 1992].

Promotion of pancreatic acinar cell tumors via CCK

In addition, the suggestion that trypsin inhibition-induced pancreatic acinar cell tumor formation is promoted by increased acinar cell proliferation via CCK receptors is supported by the following study. After initiating treatment with 30 mg/kg azaserine at 19 days of age, rats were treated with camostat, CCK8, or gelatin control, in combination with or without the CCK receptor antagonist CR-1409 (once daily, 3 days/week for 16 weeks). After 16 weeks, both camostat and CCK8 stimulated pancreatic growth and the development of azaserine-induced acidophilic putative preneoplastic foci. CR-1409 almost completely abolished the effect of CCK8 and significant attenuated the effect of camostat [Douglas BR et al, 1

Soybean trypsin inhibitor

KE4/AO:

Soy and potato trypsin inhibitor (TI) concentrates were prepared from defatted raw soy flour and potato juice. Rats and mice were fed a diet supplemented with each concentrate to provide 100 and 200 mg of trypsin inhibitor activity per 100 g of diet. In short-term (28 d) experiments in rats, both sources of TI induced pancreatic hypertrophy (KE4). After long-term feeding (95 weeks) in rats, soy and potato TI induced dose-related increases in pancreatic nodular hyperplasia and acinar adenoma (AO) [Gumbmann MR et al, 1989].

Rats were continuously fed diets containing lower amounts of raw soya flour (RSF, 5%, 25% and 50%) with weekly intraperitoneal injection of either azaserine at 5mg/kg BW or saline for up to 85 weeks or were fed RSF intermittently (2 days per week).After a maximum of 2 years of study, continuous feeding of as little as 5% RSF developed pancreatic micro/macroscopic nodules and stimulated the development of azaserine-initiated nodular hyperplasia and tumorigenesis. Intermittent feeding of 25 , 50 and 100% RSF also induced nodular hyperplasia. In addition, consuming a 100% RSF diet for 2 days per week resulted in the development of pancreatic cancer in some of the rats [McGuinness EE and Wormsley KG, 1986].

Protease inhibitor camostat:

KE4:

Adult Fischer 344 (F344) and Lewis rats fed camostat mixed in the diet to define a level that induced pancreatic hypertrophy and hyperplasia. As little as 0.02% fed 3 days per week was effective [Lhoste EF et al, 1988].

AO:

F344 rats were injected s.c. twice with azaserine at 30 mg/kg BW and thereafter were given camostat at 200 mg/kg BW by gavage 5 days a week until autopsy 18 weeks later. In addition, azaserine-treated Lewis rats were fed camostat in the diet at 0.5 g/kg diet for 4 weeks and then 0.2 g/kg diet 3 consecutive days a week for 8 or 16 weeks until autopsy. In these experiments the number and size of atypical acinar cell foci and nodules (AACN) were increased in comparison with the control groups. The data suggest a promoting effect of dietary camostat on the growth of azaserine-induced preneoplastic lesions in the pancreas of both rat strains [Lhoste EF et al, 1988].

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Sustained pancreatic growth (acinar cell proliferation) leading to acinar cell tumor formation

Rats fed a diet containing raw soya flour developed micro- and macro-nodules. Longer treatment with raw soya flour resulted in further growths in the pancreas and, ultimately, development of adenomas and carcinomas in the acinar pancreas. The pancreatic changes were reversible up to 6 months of consuming the raw soya flour diet but became irreversible thereafter [McGuinness EE et al, 1985].

Soybean trypsin inhibitor

KE4/AO:

Soy and potato trypsin inhibitor (TI) concentrates were prepared from defatted raw soy flour and potato juice. Rats and mice were fed a diet supplemented with each concentrate to provide 100 and 200 mg of trypsin inhibitor activity per 100 g of diet. In short-term (28 d) experiments in rats, both sources of TI induced pancreatic hypertrophy (KE4). After long-term feeding (95 weeks) in rats, soy and potato TI induced dose-related increases in pancreatic nodular hyperplasia and acinar adenoma (AO) [Gumbmann MR et al, 1989].

Rats were continuously fed diets containing lower amounts of raw soya flour (RSF, 5%, 25% and 50%) with weekly intraperitoneal injection of either azaserine at 5mg/kg BW or saline for up to 85 weeks or were fed RSF intermittently (2 days per week).After a maximum of 2 years of study, continuous feeding of as little as 5% RSF developed pancreatic micro/macroscopic nodules and stimulated the development of azaserine-initiated nodular hyperplasia and tumorigenesis. Intermittent feeding of 25 , 50 and 100% RSF also induced nodular hyperplasia. In addition, consuming a 100% RSF diet for 2 days per week resulted in the development of pancreatic cancer in some of the rats [McGuinness EE and Wormsley KG, 1986].

Protease inhibitor camostat:

KE4:

Adult Fischer 344 (F344) and Lewis rats fed camostat mixed in the diet to define a level that induced pancreatic hypertrophy and hyperplasia. As little as 0.02% fed 3 days per week was effective [Lhoste EF et al, 1988].

AO:

F344 rats were injected s.c. twice with azaserine at 30 mg/kg BW and thereafter were given camostat at 200 mg/kg BW by gavage 5 days a week until autopsy 18 weeks later. In addition, azaserine-treated Lewis rats were fed camostat in the diet at 0.5 g/kg diet for 4 weeks and then 0.2 g/kg diet 3 consecutive days a week for 8 or 16 weeks until autopsy. In these experiments the number and size of atypical acinar cell foci and nodules (AACN) were increased in comparison with the control groups. The data suggest a promoting effect of dietary camostat on the growth of azaserine-induced preneoplastic lesions in the pancreas of both rat strains [Lhoste EF et al, 1988].

TBD

Hypertrophy/hyperplasia of acinar cells and tumor development in rats fed TI-containing diet were examined in the same rat study reported as follows:

Weanling male Wistar rats were fed 15 diets consisting of four concentrations of purified soybean TIs (93, 215, 337, and 577 mg/100 g diet) and three protein concentrations (10%, 20%, and 30%), as well as raw and heat-treated soy flour containing 10% protein. Rats were first sacrificed at 6 months and at 3-month intervals thereafter over a period of 22 months [Rackis JJ et al, 1985]. In this study, the following dose responses for KE4 and AO were obtained.

KE4: Hypertrophy and hyperplasia of the pancreas determined by pancreas weight and RNA and DNA content developed at 6 months and were likewise positively correlated with the levels of TI and protein. Although the hypertrophic response remained unchanged, hyperplasia became more pronounced as the period of exposure to TI was prolonged [Liener IE et al, 1985].

AO: Nodular hyperplasia of acinar cells was observed in the first sacrifice group at 6 months. Incidence of the lesion was positively related to both time of exposure and level of dietary TI. Acinar cell adenoma was first observed at 18 months and was most prevalent in rats fed the highest concentration of TI [Spangler WL et al, 1985].

KE4:

Several studies have suggested that acinar cell proliferation is induced approximately 7 days after treatment with TIs or CCK. Rats fed RSF showed a biphasic increase in the proliferation of acinar and duct cells on days 2–4 and again on days 7–28 after the start of RSF feeding. The first peak may represent a regenerative response to tissue damage. The second more delayed peak appears to represent the development of hyperplasia in response to a trophic stimulus [Oates PS and Morgan RG, 1984]. Rats administered TIs in drinking water for 7 days or repeatedly injected with CCK for 7 days exhibited increased mitotic figures in the acinar, centroacinar, and intercalated portions of the pancreas and in excretory duct cells, as well as marked pancreatic hypertrophy [Yanatori Y and Fujita T, 1976].

AO:

Increased CCK-mediated acinar cell proliferation might lead to acinar cell tumor formation, as shown by the following findings: In rats fed soybean TIs, acinar cell hyperplasia was observed at the first sacrifice time point (6 months) and became more pronounced with prolonged TI exposure. Nodular hyperplasia of acinar cells was also found at 6 months and increased at later dosing periods. Acinar cell adenomas were first observed at 18 months of TI exposure [Liener IE et al, 1985; Spangler WL et al, 1985].

Morgan et al. reported that rats fed an RSF diet for 24 weeks developed pancreatic hypertrophy and hyperplasia, as determined by DNA, RNA, and protein contents in the pancreas, and developed more pronounced azaserine (30 mg/kg once a week for 5 weeks)-induced nodular hyperplasia compared with rats fed a heat-treated soy flour diet [Morgan RG et al, 1990].

TBD