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Relationship: 2032
Title
Acinar cell proliferation leads to Acinar cell tumors
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Trypsin inhibition leading to pancreatic acinar cell tumors | adjacent | High | High | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
An increased blood level of CCK is the main factor responsible for a sustained increase in acinar cell proliferation and subsequent tumor formation.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
TBD
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].
TBD
Response-response Relationship
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
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 Feedforward/Feedback loops influencing this KER
TBD
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.