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Event: 1725

Key Event Title

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Pancreatic acinar cell tumors

Short name
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Acinar cell tumors
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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TI-induced AC tumors AdverseOutcome Arthur Author (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
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

Life Stages

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Life stage Evidence
All life stages High

Sex Applicability

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Term Evidence
Mixed High

Key Event Description

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Several reports have shown that increased blood CCK levels directly stimulate acinar cell proliferation via CCK1 receptors in rats as follows:

In rats with a sustained increase in the CCK level due to treatment with a CCK1 receptor agonist (CCK-8), acinar cell proliferation and pancreatic hypertrophy were induced [Folsch UR et al, 1978; Povoski SP et al, 1994]. Endogenous and exogenous increases in blood CCK levels induced pancreatic hypertrophy due to the direct action of CCK on acinar cells [Yamamoto M et al, 2003]. Repeated administration of the CCK1 receptor agonist GI181771X to rats and mice resulted in pancreatic injury, hypertrophy and diffuse/focal hyperplasia of acinar cells, and zymogen degranulation depending on the dose and dosing period [Myer JR et al, 2014].

Administration of the trypsin inhibitor A8947 to rats increased pancreatic weight; however, infusion of the selective CCK1 receptor antagonist MK-329 using an osmotic minipump completely diminished this effect of A8947 on pancreatic weight [Obourn JD et al, 1997].

These results indicate that CCK directly stimulates pancreatic acinar cell proliferation via CCK1 receptors, and trypsin inhibition enhances acinar cell proliferation due to an increased plasma level of CCK.

How It Is Measured or Detected

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Pancreatic acinar cell proliferation is evaluated based on measurements of pancreatic weight and DNA and RNA levels [Folsch UR et al, 1978; Povoski SP et al, 1994; Tashiro M et al, 2004], as well as histopathological examination [Povoski SP et al, 1994]. In these experiment, pancreatic weight, protein content, RNA content, DNA content, protein-DNA ratio, RNA-DNA ratio, pancreatic area per nucleus, and number of mitoses per 10,000 acinar cells could be determined. Among such parameters, Increased DNA content and number of mitoses per 10,000 acinar cells are indicative of acinar cell hyperplasia, and the others suggest pancreatic or acinar cell hypertrophy and increased pancreatic protein synthesis.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

In monkeys receiving repeated dosing of the CCK1 receptor agonist GI181771X for up to 52 weeks, no hypertrophy or histopathological changes of the pancreas were observed, but these results differed from those of rats [Myer JR et al, 2014]. In humans, obese patients treated with GI181771X for 24 weeks showed no abnormal changes in the pancreas by ultrasonography or MRI [Jordan J et al, 2008]. On the other hand, oral ingestion of raw soya flour, which contains trypsin inhibitors, increased the release of CCK in humans [Calam J et al, 1987]. In addition, some epidemiological studies reported that the incidence of pancreatic tumors in humans administered high levels of protease inhibitors was decreased [Messina M and Messina V, 1991; Miller RV, 1978]. These results suggest no relevance between pancreatic growth/tumor development and CCK-agonist treatment in humans or non-human primates.

As indicated above, the effects of CCK on acinar cell proliferation differ between rodents and humans. In rodents, proliferation of pancreatic acinar cells is regulated directly via CCK1 receptors expressed on their surfaces. However, in humans, CCK1 receptor density on the surface of pancreatic acinar cells is low, and exocrine secretion is innervated by vagal afferent nerves, with little effect on acinar cell proliferation.

Regulatory Significance of the Adverse Outcome

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References

List of the literature that was cited for this KE description. More help

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

 2.    Folsch UR, Winckler K, Wormsley KG: Influence of repeated administration of cholecystokinin and secretin on the pancreas of the rat. Scand J Gastroenterol 13:663-671,1978

 3.    Jordan J, Greenway FL, Leiter LA, Li Z, Jacobson P, Murphy K, Hill J, Kler L, Aftring RP: Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients. Clin Pharmacol Ther 83:281-287,2008

 4.    Messina M, Messina V: Increasing use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc 91:836-840,1991

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

 6.    Myer JR, Romach EH, Elangbam CS: Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys. Toxicol Pathol 42:260-274,2014

 7.    Obourn JD, Frame SR, Chiu T, Solomon TE, Cook JC: Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism. Toxicol Appl Pharmacol 146:116-126,1997

 8.    Povoski SP, Zhou W, Longnecker DS, Jensen RT, Mantey SA, Bell RH Jr: Stimulation of in vivo pancreatic growth in the rat is mediated specifically by way of cholecystokinin-A receptors. Gastroenterology 107:1135-1146,1994

 9.    Tashiro M, Samuelson LC, Liddle RA, Williams JA: Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286:G784-790,2004

10.    Yamamoto M, Otani M, Jia DM, Fukumitsu K, Yoshikawa H, Akiyama T, Otsuki M: Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats. Am J Physiol Gastrointest Liver Physiol 285:G681-687,2003