Pancreatobiliary diversion enhances experimental pancreatic carcinogenesis

Abstract

Summary Since compensatory hyperplasia promotes experimental carcinogenesis in the gut, we tested the ability of two surgical models of pancreatic growth to promote pancreatic carcinogenesis. Male Wistar rats (n = 60) weighing 250 -300 g underwent pancreatobiliary diversion (PBD), 90% small bowel resection (PSBR) or triple transection and reanastomosis of the small intestine (controls). Postoperatively, each group received azaserine (20 mg kg-' wk-' i.p.) for 6 weeks. Surviving rats were killed at 6 months, pancreatic wet weight was measured and histological sections were examined for atypical acinar cell foci (AACF), the putative precursor of carcinoma. Median relative pancreatic weight (mg pancreas/g body weight) was 2.20 for controls (n = 18), 4.08 for PSBR (n = 11) (P <0.001) and 6.86 for PBD (n = 16) (P <0.001). PSBR did not affect the development of acidophilic AACF, but PBD produced an enormous increase in their number per cm3 (median 96 vs 0; P <0.001) and a 7-fold increase in their volume (P <0.001). Both operations cause pancreatic growth, but only PBD promotes carcinogenesis, possibly because of its unique hormonal effect.In the oesophagus, stomach and large intestine, carcinogenesis can be enhanced by luminal factors acting directly on the mucosa, but in the pancreas any such influence (particularly dietary) must be exerted indirectly through hormonal and/or neural connections, i.e. via the enteropancreatic axis. Presumably this type of pathway accounts for the correlation between a high-fat diet and pancreatic cancer mortality (Wynder et al., 1973). In the stomach and colon, hyperplasia precedes and predisposes to neoplasia (Williamson & Rainey, 1984), and the same could be true for the pancreas. Feeding raw soya flour causes hyperplasia of the pancreas in rats and potentiates the carcinogenic effect of azaserine (McGuiness et al., 1981).Pancreatic growth can be stimulated by surgical operations. Thus transposition of a long segment of jejunum to lie between the pylorus and duodenal papilla will cause marked hyperplasia of rat pancreas within 7 days (Stace et al., 1987). This effect may be mediated by an increased secretion of cholecystokinin (CCK) from the jejunum in the absence of pancreatic juice (Miazza et al., 1987). Another surgical stimulus to pancreatic growth in rats is massive (90%) small bowel resection, though here the mechanism is unclear (Stock-Damge et al., 1984): neither CCK nor gastrin appear to be involved.The present study tests the hypothesis that surgical stimulation of pancreatic growth will enhance carcinogenesis. We have used pancreatobiliary diversion and subtotal enterectomy to manipulate the enteropancreatic axis and the formation of acidophilic AACF (atypical acinar cell foci) to indicate early malignant change (Roebuck et al., 1984 tion; the proximal 90% of the jejunoileum was excised with an end-to-end anastomosis between the duodenojejunal flexure and the terminal 5 cm of ileum. The second group (PBD) received pancreatobiliary diversion as previously described (Stace e...

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion

“…Our data confirm the potent effect of pancreatobiliary diversion in enhancing experimental pancreatic carcinogenesis and strongly support the hypothesis that hyperchlecystokininaemia is the key intermediary (Miazza et al, 1987;Stewart et al, 1991;Watanapa et al, 1991). Not only were circulating CCK levels elevated after PBD, but in addition the specific antagonist CR-1409 sharply diminished the number of acidophilic AACF.…”

“…In line with Douglas and colleagues (1989), our finding that CR-1409 reduced both pancreatic weight and the number of AACF supports the association between hyperplasia and neoplasia. To the contrary, one stimulus (massive enterectomy) can cause pancreatic growth without promoting cancer (Stewart et al, 1991), while another (exogenous caerulein) can cause the reverse (Lhoste & Longnecker, 1987). Thus the co-carcinogenic effect of PBD might be partly independent of its growth-promoting effect and could reflect a direct action of CCK on malignant transformation of the exocrine pancreas.…”

“…The associated hypercholecystokininaemia plus the inhibitory effect of the CCK anatagonist CR-1409 indicate the pivotal role of CCK in the adaptive response to pancreatobiliary diversion (PBD) . Our long-term study in rats showed that both PBD and massive small bowel resection will stimulate pancreatic growth, but only PBD enhances pancreatic carcinogenesis (Stewart et al, 1991); CCK levels were not measured in this experiment.…”

“…The actual numerical lower limits adopted were 0.0005 mm2 for basophilic AACF and 0.01 mm2 for the acidophilic variety; these values correspond to those chosen by Roebuck et al (1984). Details of this analysis have been already described in our previous studies (Stewart et al, 1991 Some pancreatic acinar cells also showed cytoplasmic vacuoles and loss of zymogen granules. These findings were not seen in the saline-treated rats.…”

Experimental pancreatic hyperplasia and neoplasia: effects of dietary and surgical manipulation

“…The duodenum participates in this adaptive response to proximal small bowel resection (Williamson & Bauer, 1978;Urban et (Stewart et al, 1991), probably because severe weight loss and malabsorption suppressed carcinogenesis (Roebuck et al, 1981b). Thus the stimulatory effect of operation might be balanced by the inhibitory effect of caloric restriction.…”