API

Relationship: 2032

Title

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Acinar cell proliferation leads to Acinar cell tumors

Upstream event

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Acinar cell proliferation

Downstream event

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Acinar cell tumors

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Trypsin inhibition leading to pancreatic acinar cell tumors adjacent High High

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI
Macaca fascicularis Macaca fascicularis Moderate NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus Moderate NCBI

Sex Applicability

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Sex Evidence
Mixed High

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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An increased blood level of CCK is the main factor responsible for a sustained increase in acinar cell proliferation and subsequent tumor formation.

Evidence Supporting this KER

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TBD

Biological Plausibility

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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].

Empirical Evidence

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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].

Uncertainties and Inconsistencies

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TBD

Quantitative Understanding of the Linkage

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TBD

Response-response Relationship

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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].

Time-scale

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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].

Known modulating factors

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Trypsin inhibition promotes acinar cell tumor formation.

TI-enhanced growth of azaserine-induced pancreatic preneoplastic lesions were reduced especially in size by the CCK receptor antagonist lorglumide (CR-1409) [Douglas BR et al, 1989].

Pancreatic growth was induced by cholestyramine, similar to that by TIs, presumably because of the bile salt-binding properties of cholestyramine. This finding suggests that removal of proteases and bile salts from the upper small intestine results in pancreatic growths, which may become neoplastic [McGuinness EE et al, 1985].

The thrombin inhibitor ximelagatran induced focal/multifocal acinar cell hyperplasia and adenomas in the pancreas of rats after 24 months of oral administration at 240 μmol/kg/day. However, in mice, no tumors formed after 18 months of treatment with ximelagatran. Treatment with dabigatran, which is in the same class as ximelagatran, showed no carcinogenicity in mice or rats [Stong DB et al, 2012].

Unsaturated fat (corn oil) was reported to promote the growth of azaserine-induced preneoplastic lesions and acinar cell tumors, without inducing pancreatic hypertrophy, in the rat pancreas [Woutersen RA et al, 1991].

Known Feedforward/Feedback loops influencing this KER

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TBD

Domain of Applicability

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Rats fed a diet supplemented with soy and potato TI concentrates for 28 days developed pancreatic hypertrophy, and after long-term feeding (95 weeks), the rats developed nodular hyperplasia and acinar adenoma in a dose-dependent manner. Although mice responded similarly to rats to soy TIs in short-term (28 days) feeding experiments, they did not form these pathologies (hyperplasia or acinar adenoma) following long-term feeding. This considerable species difference suggests that the propensity to develop preneoplastic and neoplastic lesions in the pancreas is not predicted by short-term pancreatic hypertrophic and hyperplastic responses to TIs [Gumbmann MR et al, 1989].

The effects of TI-containing diets were evaluated in rats, mice, and hamsters for 30 weeks. In rats and mice, pancreatic weight and DNA, RNA, and protein levels increased in response to a diet consisting of RSF (which contains TIs). Only rats fed RSF developed reversible micro- and macro-nodules after 6 months of treatment, and longer treatment with RSF resulted in further growth in the pancreas and, ultimately, development of adenomas and carcinomas from pancreatic acinar cells [McGuinness EE et al, 1985].

The reasons for the abovementioned species differences in tumor outcome based on hyperplastic changes in acinar cells are unclear, even in rodents.

Meanwhile, a strong relationship between pancreatic cancer and a history of subtotal gastrectomy [Mack TM et al, 1986], which induced a higher plasma CCK level in response to fat [Hopman WP et al, 1984], was reported. On the other hand, some epidemiological surveys suggested that long-term ingestion of TI-containing foods does not increase the risk of pancreatic cancer [Miller RV, 1978], although oral ingestion of raw soya flour containing TIs was reported to stimulate CCK release in humans [Calam J et al, 1987]. Therefore, the effect of CCK on acinar cell proliferation in humans is controversial.

In cases where acinar cell proliferation is enhanced due to a certain treatment, the risk of acinar cell tumor formation may be high in humans as well as rodents.

References

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 1.    Bell RH Jr, Kuhlmann ET, Jensen RT, Longnecker DS: Overexpression of cholecystokinin receptors in azaserine-induced neoplasms of the rat pancreas. Cancer Res 52:3295-3299,1992

 2.    Calam J, Bojarski JC, Springer CJ: Raw soya-bean flour increases cholecystokinin release in man. Br J Nutr 58:175-179,1987

 3.    Douglas BR, Woutersen RA, Jansen JB, de Jong AJ, Rovati LC, Lamers CB: Modulation by CR-1409 (lorglumide), a cholecystokinin receptor antagonist, of trypsin inhibitor-enhanced growth of azaserine-induced putative preneoplastic lesions in rat pancreas. Cancer Res 49:2438-2441,1989

 4.    Gumbmann MR, Spangler WL, Dugan GM, Rackis JJ: Safety of trypsin inhibitors in the diet: effects on the rat pancreas of long-term feeding of soy flour and soy protein isolate. Adv Exp Med Biol 199:33-79,1986

 5.    Gumbmann MR, Dugan GM, Spangler WL, Baker EC, Rackis JJ: Pancreatic response in rats and mice to trypsin inhibitors from soy and potato after short- and long-term dietary exposure. J Nutr 119:1598-1609,1989

 6.    Hopman WP, Jansen JB, Lamers CB: Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy. Ann Surg 199:276-280,1984

 7.    Lhoste EF, Roebuck BD, Longnecker DS: Stimulation of the growth of azaserine-induced nodules in the rat pancreas by dietary camostate (FOY-305). Carcinogenesis 9:901-906,1988

 8.    Liener IE, Nitsan Z, Srisangnam C, Rackis JJ, Gumbmann MR: The USDA trypsin inhibitor study. II. Timed related biochemical changes in the pancreas of rats. Qual Plant Foods Hum Nutr 35:243-257,1985

 9.    Mack TM, Yu MC, Hanisch R, Henderson BE: Pancreas cancer and smoking, beverage consumption, and past medical history. J Natl Cancer Inst 76:49-60,1986

10.    McGuinness EE, Morgan RG, Wormsley KG: Trophic effects on the pancreas of trypsin and bile salt deficiency in the small-intestinal lumen. Scand J Gastroenterol Suppl 112:64-67,1985

11.    McGuinness EE, Wormsley KG: Effects of feeding partial and intermittent raw soya flour diets on the rat pancreas. Cancer Lett 32:73-81,1986

12.    Miller RV: Epidemiology. Alan R. Liss, New York (pp) 39-57,1978

13.    Morgan RG, Papadimitriou JM, Crass RA: Potentiation of azaserine by cholestyramine in the rat. Int J Exp Pathol 71:485-491,1990

14.    Oates PS, Morgan RG: Short-term effects of feeding raw soya flour on pancreatic cell turnover in the rat. Am J Physiol 247:G667-73,1984

15.    Rackis JJ, Gumbmann MR, Liener IE: The USDA trypsin inhibitor study. I. Background, objectives, and procedural details. Qual Plant Foods Hum Nutr 35:213-24,1985

16.    Spangler WL, Gumbmann MR, I.E. Liener IE, J.J. Rackis JJ: The USDA trypsin inhibitor study. III. Sequential development of pancreatic pathology in rats. Qual Plant Foods Hum Nutr 35:259-274 ,1985

17.    Stong DB, Carlsson SC, Bjurstrom S, Fransson-Steen R, Healing G, Skanberg I: Two-year carcinogenicity studies with the oral direct thrombin inhibitor ximelagatran in the rat and the mouse. Int J Toxicol 31:348-357,2012

18.    Woutersen RA, van Garderen-Hoetmer A, Lamers CB, Scherer E: Early indicators of exocrine pancreas carcinogenesis produced by non-genotoxic agents. Mutat Res 248:291-302,1991

19.    Yanatori Y, Fujita T: Hypertrophy and hyperplasia in the endocrine and exocrine pancreas of rats fed soybean trypsin inhibitor or repeatedly injected with pancreozymin. Arch Histol Jpn 39:67-78,1976