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Gut peptides are involved in the growth and carcinogenesis of the exocrine pancreas of rats after treatment with azaserine. However, little is known about the influence of azaserine on expression of gut peptide receptors in the pancreas of the rat. Cholecystokinin, bombesin, somatostatin, secretin and vasoactive intestinal peptide receptors were therefore visualized and quantified by storage phosphor autoradiography in pancreata of either saline control or azaserine-treated rats. As expected, putative preneoplastic lesions were formed in the pancreata of the azaserine-treated but not in the control animals. The pancreata of control rats contained receptors for cholecystokinin, bombesin, somatostatin, secretin and vasoactive intestinal peptide. Cholecystokinin receptors were of the A-type and showed, in contrast to the other receptors, a heterogeneous expression due to variability of the high-affinity receptors. In the pancreata of azaserine-treated animals a significantly increased binding capacity of high-affinity receptors for cholecystokinin was found not only in atypical acinar cell nodules but also in non-nodular pancreas when compared to pancreas of control rats (P < 0.05). Neither atypical acinar cell nodules nor non-nodular pancreas of rats treated by azaserine were shown to possess receptors for the other four types of gut peptide receptors. The spectrum of peptide receptors in pancreas of control and azaserine-treated rats in this study may help to understand the mechanism whereby gut hormones may modulate pancreatic carcinogenesis.

The present study was performed to assess the effects of diets supplemented with low (5%) and high (20%) corn oil on a Pts 56 retrovirus-induced model of pancreatic carcinogenesis in guinea fowl. The early microscopic lesions appear after 3 mo after virus treatment and progress over time. Eight to 10 mo after initiation, up to 100% of virus-inoculated birds develop multiple hyperplastic and neoplastic pancreatic lesions of duct/ductular phenotype. Short-term (1-4 mo) feeding of low- or high-fat diets, beginning at Month 3, had no significant effects on body and pancreatic weight. However, the incidence, multiplicity, and areas of the pancreatic tissue occupied by intra- and interlobular aggregates of hyperplastic ducts with mucinous metaplasia of the lining cells were significantly increased compared with the birds fed the common diet. At the same time, development of ductular neoplasms, particularly carcinomas, was retarded compared with the common diet-fed controls. Long-term (5-7 mo) fat intake resulted in an increase in body weight gain, while absolute pancreatic weights remained relatively constant. Furthermore, the high- and low-fat diets caused a significant increase in areas of retrovirus-induced pancreatic lesions, as well as an increase in multiplicity of ductular neoplasms compared with short-term fat feeding. It is concluded that short-term feeding of diets supplemented with 5% or 20% corn oil delayed the development of the common virus-induced ductular neoplasms, particularly carcinomas, and had an enhancing effect on development of hyperplastic inter- and intralobular aggregates of ducts. This finding was not observed, however, during the long-term feeding period of the study.

Angiogenesis is the formation of new blood vessels from preexisting ones. Many solid tumors depend on an extensive newly formed vascular network to become nourished and to expand. Tumor cells induce the formation of an extensive but aberrant vascular network by the secretion of angiogenic factors. A proper context is needed for the endothelial cells to respond. To create this proper context, the tumor often uses the body's own repair system to accelerate angiogenesis and the subsequent tumor expansion. The angiogenic response is governed by the interaction of angiogenic growth factors and cytokines with specific receptors on the endothelium, as well as by the interaction of these cells with their surrounding matrix, which is regulated by matrix-degrading proteases and adhesion molecules such as integrins. A number of agents have been discovered and developed that aim to inhibit angiogenesis and to convert the tumor to a dormant state. They have proven to be effective in animal studies. At present their efficacy in man is under evaluation.

The effects of vitamins E and E, β-carotene and selenium on development of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumours in hamsters were investigated. Dietary supplementation of vitamin C, alone as well as in combination with β-carotene resulted in consistently lower numbers of advanced ductular lesions. The differences with the controls, however, did not reach the level of statistical significance. β-carotene alone demonstrated no inhibitory effect on the development of (pre)neoplastic lesions in the pancreas. Vitamin E or Se, either alone or in combination, had no effect on the development of advanced ductular lesions in BOP-treated hamsters. Chemicals/CAS: Ascorbic Acid, 50-81-7; beta Carotene, 7235-40-7; Carcinogens; Carotenoids, 36-88-4; Nitrosamines; nitrosobis(2-oxopropyl)amine, 60599-38-4; Selenium, 7782-49-2; Vitamin E, 1406-18-4

This study investigates the possibility that the c-Src protein tyrosine kinase is involved in experimental exocrine pancreatic carcinogenesis. Expression and activity of the protooncogene pp60c-src (c-Src) are investigated in acinar pancreatic (pre-) neoplastic lesions induced in rats by azaserine and compared with normal rat pancreas. Low or absent c-Src immunoreactivity and c-Src tyrosine kinase activity were found in the pancreas of untreated control rats. Compared with these controls, c-Src protein immunoreactivity was increased in "normal" acinar cells and even more in putative preneoplastic atypical acinar cell nodules (AACN) after azaserine treatment. In contrast, more advanced (secondary transformed) acinar cell lesions demonstrated no c-Src immunoreactivity. Rats treated with azaserine showed a 7-fold-higher c-Src tyrosine kinase activity in their pancreas. The level of c-Src tyrosine kinase activity correlated positively with the number of lesions in the pancreas, inasmuch as promotion of azaserine-initiated carcinogenesis by cerulein resulted in a more than 10-fold increase in the number of AACN, which was accompanied by a 6-fold increase in c-Src activity when compared with azaserine treatment alone. c-Src tyrosine kinase activity was responsible, on average, for 40% of the total tyrosine kinase activity in the pancreatic homogenates and was predominantly found in the cytoskeletal subcellular fraction. Furthermore, the transformation from normal to preneoplastic pancreatic tissue in azaserine-treated rats was accompanied by a change in the localization of the c-Src protein. With the use of immunohistochemistry and confocal laser scanning microscopy, the protein was detected in the cytoplasm in morphologically normal pancreatic acini, whereas in AACN it was detected both in the cytoplasm and in the nuclei. It is concluded that the protooncogene c-Src might be involved early in experimental pancreatic carcinogenesis: c-Src probably plays a minor role in pancreatic acinar cells after transformation to malignancy. Chemicals/CAS: Protein-Tyrosine Kinases, EC 2.7.1.112; Proto-Oncogene Proteins pp60(c-src), EC 2.7.1.112

The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via cholecystokinin. Chemicals/CAS: azaserine, 115-02-6; cholecystokinin, 9011-97-6, 93443-27-7; lorglumide, 97964-56-2; Azaserine, 115-02-6; Cholecystokinin, 9011-97-6; Dietary Fats; lorglumide, 97964-56-2; Proglumide, 6620-60-6; Receptors, Cholecystokinin

In the present study the chemopreventive potential of 25% fat (HF) diets containing 2 wt% linoleic acid (LA) and including 0.0, 1.2, 2.4, 4.7, 7.1 or 9.4 wt% dietary fish oil (MaxEPA) has been investigated using the N-nitrosobis(2-oxopropyl)amine (BOP)-hamster model for pancreatic cancer. The number of pancreatic borderline lesions (BLL) was significantly higher (P < 0.05) in the HF groups containing 1.2, 2.4 or 9.4 wt% MaxEPA in comparison with the HF group without MaxEPA. MaxEPA inhibited the metabolism of LA to arachidonic acid (AA) and of AA to prostaglandins (PGs) in both blood plasma and pancreatic microsomes. The pancreatic levels of PGE2 (P < 0.05), 6-keto-PGF(1α), (P < 0.01) and PGF(2α) (P < 0.05) decreased significantly with increasing dietary MaxEPA. The levels of PGE2 (P < 0.001), 6-keto-PGF(1α) (P < 0.05), PGF(2α) (P < 0.001) and thromboxane (TX) B2 (P < 0.001) in pancreatic adenocarcinomas were higher than in non-tumorous pancreas. The MaxEPA had no significant effect on the BrdU labeling index (LI) in acinar, ductular or centroacinar cells, nor on the LI in BOP-induced pancreatic lesions. It is concluded that (i) dietary fish oil has a slight enhancing effect on POP-induced pancreatic carcinogenesis in hamsters and (ii) dietary fish oil dose-dependently inhibits the conversion of LA to AA and of AA to certain PGs and (iii) dietary fish oil does not influence the cell proliferation in hamster pancreas.

The present 12-month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and N-nitrosobis(2-oxopropyl)amine-treated hamsters. Treatment of the animals started 4 months after the last injection with the carcinogen. They were surgically castrated and/or treated with aminoglutethimide. Aminoglutethimide-treated rats developed less pancreatic tumours than did untreated controls. Multiplicity of (pre-)-neoplastic acinar lesions was lower in orchiectomized rats than in intact rats. Inhibition of pancreatic carcinogenesis was most pronounced in rats that were both orchiectomized and treated with aminoglutethimide. These effects were statistically significant after 8 months, but not after 4 months, of treatment. In hamsters, aminoglutethimide showed an enhancing rather than an inhibitory effect on the formation of ductular pancreatic tumours. Castration appeared to have no effect on the development of N-nitrosobis(2-oxopropyl)amine-induced ductular lesions in the pancreas, either alone, or in combination with aminoglutethimide. The present findings indicate that aminoglutethimide, alone and in combination with surgical castration, might be of value for the treatment of pancreatic acinar tumours, whereas the usefulness of aminoglutethimide for treatment of ductular adenocarcinomas of the pancreas is somewhat doubtful.

Fruit and vegetable intake may protect against pancreatic cancer, since fruits and vegetables are rich in potentially cancer-preventive nutrients. Most case-control studies have found inverse associations between fruit and vegetable intake and pancreatic cancer risk, although bias due to reporting error cannot be ruled out. In most prospective studies, inverse associations have been weaker and imprecise because of small numbers of cases. The authors examined fruit and vegetable intake in relation to pancreatic cancer risk in a pooled analysis of 14 prospective studies from North America, Europe, and Australia (study periods between 1980 and 2005). Relative risks and 2-sided 95 confidence intervals were estimated separately for the 14 studies using the Cox proportional hazards model and were then pooled using a random-effects model. Of 862,584 men and women followed for 7-20 years, 2,212 developed pancreatic cancer. The pooled multivariate relative risks of pancreatic cancer per 100-g/day increase in intake were 1.01 (95 confidence interval (CI): 0.99, 1.03) for total fruits and vegetables, 1.01 (95 CI: 0.99, 1.03) for total fruits, and 1.02 (95 CI: 0.99, 1.06) for total vegetables. Associations were similar for men and women separately and across studies. These results suggest that fruit and vegetable intake during adulthood is not associated with a reduced pancreatic cancer risk. © 2012 The Author.

Epidemiologic investigations have suggested a relationship between dietary fat intake and various types of cancer incidences. Furthermore, epidemiologic studies as well as studies with animal models have demonstrated that not only the amount but also the type of fat consumed is important. At present, the mechanism by which dietary fat modulates carcinogenesis has not been elucidated. The effects of dietary fat on the development of tumours have been summarized in the present review with emphasis on colorectal, pancreas, breast and prostate cancer. It is concluded that influence on synthesis of prostaglandins and leukotrienes may be the universal mechanism by which dietary fats modulate carcinogenesis. Copyright (C) 1999 Elsevier Science B.V.

In a previous short-term study (4 months) we found that Sandostatin, when administered prophylactically, inhibited growth of putative pre-neoplastic ductular lesions induced in hamster pancreas by N-nitrosobis(2-oxopropyl)amine (BOP), but not of acinar lesions induced in rat pancreas by azaserine. The present long-term (12 months) study was carried out to investigate the effects of Sandostatin (3 μg/day), alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and BOP-treated hamsters. In order to mimic therapy in humans, treatment of the animals started 4 months after the last injection with carcinogen, when (pre)neoplastic lesions had already developed. After treatment with Sandostatin for 8 months, rats developed fewer pancreatic atypical acinar cell nodules and tumours than those not treated with Sandostatin. Moreover, multiplicity of (pre)neoplastic acinar lesions was also lower in orchiectomized rats than in intact rats. However, Sandostatin treatment did not enhance the inhibitory effect of surgical castration on pancreatic carcinogenesis in rats. In hamsters that were both orchiectomized and treated with Sandostatin, the development of borderline lesions was significantly inhibited, whereas such an effect was not present in hamsters that were either surgically castrated or treated with Sandostitin alone. In Sandostatin-treated hamsters a significantly lower number of microcarcinomas was found than in hamsters not treated with Sandostatin. The present findings suggest that Sandostatin, particularly in combination with surgical castration, might be of therapeutic value for treatment of ductular pancreatic tumours. Chemicals/CAS: Anticarcinogenic Agents; Azaserine, 115-02-6; Carcinogens; Nitrosamines; nitrosobis(2-oxopropyl)amine, 60599-38-4; Octreotide, 83150-76-9

The present study was performed to investigate the influence of fish oil on the genotoxic effects of azaserine, using the formation of micronucleated erythrocytes as a measure for the degree of initiating potency and the number and size of putative preneoplastic pancreatic atypical acinar cell foci (AACF) as a measure for the actual number of initiated cells. Male Wistar rats were treated twice i.p. with 30 mg azaserine per kg body weight to induce AACF. During the initiation/early promotion phase the rats were maintained on diets containing 5 wt% vegetable oil (safflower and high-oleic sunflower oil), 25 wt% vegetable oil, 25 wt% fat (15% vegetable oil + 10 wt% fish oil), or 25 wt% fat (5% vegetable oil + 20 wt% fish oil), respectively. One day after carcinogen treatment, the numbers of micronucleated polychromatic erythrocytes were determined in blood smears obtained from 10 animals per group. Each high-fat diet resulted in higher percentages of micronucleated polychromatic erythrocytes than the low-fat diet. Dietary fish oil did not significantly influence the number of micronucleated cells. Two weeks after carcinogen treatment, the diets containing fish oil were replaced by the diet containing 25% vegetable oil, and the animals were further maintained for about 14 wk. Pancreatic tissue slides were microscopically evaluated for the number and size of AACF. Dietary fish oil caused an increase in the number and size of AACE although a clear dose-effect relationship was absent. It was concluded that a high level of dietary fish oil, when given during the induction/early promotion phase, enhances azaserine-induced pancreatic carcinogenesis in rats.

An association between high intake of folate and reduced risk of cancer has been suggested by previous research. However, epidemiologic data from cohort studies regarding the relationship between dietary folate and pancreatic cancer are sparse and inconsistent. We examined the association between dietary folate intake and risk of pancreatic cancer within the Netherlands Cohort Study on diet and cancer. Men and women (120,852), ages 55 to 69 years, were recruited. Information on diet was collected at baseline by means of food frequency questionnaires, and the cohort was followed for 13.3 years. Total folate and vitamer intake were calculated using folate contents of food items derived from a validated liquid chromatography trienzyme method. Cases (n = 363) were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. A casecohort approach was used using the follow-up data of a random subcohort (n = 5,000) identified at the onset of the cohort. Multivariable hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards model. After adjusting for age, gender, smoking status, number of years smoked, number of cigarettes smoked per day, and intake of added sugar multivariate hazard ratio comparing the highest and lowest quintiles of folate intake for pancreatic cancer risk was 1.37 (confidence interval, 0.97-1.94; Ptrend = 0.07). When folate vitamers were analyzed separately, results did not show a difference in association. Our results do not support a protective association of total dietary folate or individual folate vitamers on the risk of pancreatic cancer. Copyright © 2009 American Association for Cancer Research.

Diet has been hypothesized to play a role in the etiology of gastrointestinal cancer for a long time. Initially, strong evidence of such effects was found in retrospective epidemiological studies. Dietary habits, in particular those from the distant past, are difficult to measure, however. Results from recent, prospective and larger studies of better quality did not always confirm these associations. Consumption of fruits and vegetables appear to have a modest role in the prevention of gastrointestinal cancers. In contrast, the roles of alcohol consumption and overweight on risk of gastrointestinal cancer have become much clearer. Overweight and obesity are important risk factors for adenocarcinoma (but not squamous carcinoma) of the esophagus, gastric cardia carcinoma (but not noncardia carcinoma), and colorectal cancer, the latter in particular among men. Alcohol consumption is a risk factor for squamous carcinoma (but not adenocarcinoma) of the esophagus, gastric cancer and colorectal cancer. Selenium may be inversely related to esophageal and gastric cancer. © 2006 Elsevier Ltd. All rights reserved.

The effects of a diet enriched with 25% raw soya bean flour (RSF) on the pancreas and on the avian retrovirus Pts 56-induced pancreatic carcinogenesis in guinea fowl were studied. It has been shown that prolonged RSF feeding of new-hatched virus-infected and uninfected guinea fowl-poults induced enlargement of the pancreas, which was less pronounced when administration of the RSF supplemented diet started at the age of 75 days. Time-dependent multifocal inter- and intralobular hyperplasia of pleomorphic ducts lined by mucin-producing epithelium in the exocrine pancreas of virus-infected guinea fowls fed a RSF supplemented diet was regularly observed. Enlargement of virus-induced ductular neoplasms has been shown only after simultaneous RSF and virus administration. Copyright (C) 1999 Elsevier Science Ireland Ltd.

Previously performed short-term (4-month) studies demonstrated that vitamins C and E, β-carotene and selenium modulate growth of early putative preneoplastic acinar lesions induced in rat pancreas by azaserine. The present paper summarizes the results of long-term studies performed with azaserine-treated rats maintained on diets high in either β-carotene, vitamins C and E or selenium. It appeared that rats given a diet high in β-carotene, vitamin C or selenium, but not vitamin E, developed fewer pancreatic tumours than controls. The chemopreventive effects of these micronutrients were most pronounced when β-carotene and/or selenium were given during the promotion phase of the carcinogenic process. Surprisingly, cell proliferation in azaserine-induced preneoplastic acinar lesions was higher in rats given β-carotene and/or selenium via the diet in comparison to controls. It is considered unlikely that any antioxidant alone can be associated with protection against cancer. It is concluded that dietary supplementation of combinations of antioxidants may have practical application in chemoprevention of cancer. Copyright (C) 1999 Elsevier Science Ltd.

In the present study the putative chemopreventive effect of dietary fish oil (MaxEPA) on azaserine-induced pancreatic carcinogenesis in rats was investigated. Groups of rats were maintained on a semipurified low-fat (LF; 5 wt%) diet or on semipurified high-fat (HF; 25 wt%) diets containing 5 wt% linoleic acid (LA) and including 0.0, 1.2, 2.4, 4.7, 7.1 or 9.4 wt% MaxEPA. Animals fed a HF diet developed significantly higher mean numbers of atypical acinar cell nodules (AACNs), adenomas and carcinomas than animals fed a LF diet. Dietary MaxEPA caused a significant (P<0.01) dose-related increase in mean number of AACNs (0.5 <θ <3.0 mm). The mean number of adenomas and carcinomas remained similar among the groups. Cell proliferation was significantly lower in AACNs from animals fed HF containing 9.4% MaxEPA in comparison with HF without MaxEPA and with LF. LA levels had increased and arachidonic acid (AA) levels had decreased in blood plasma and pancreas with increasing dietary MaxEPA. Feeding MaxEPA resulted in significant decreases in 6-keto-prostaglandin (PG) F(1α), (P<0.05) and PGF(2α) (P<0.01) in non-tumorous pancreas, whereas PGE2, PGF(2α) and thromboxane B2 (TXB2) levels were significantly (P<0.001) higher in pancreatic tumour tissue than in non-tumorous pancreatic tissue. It is concluded that (i) dietary MaxEPA enhances dose-relatedly growth of putative preneoplastic AACNs in the pancreas of azaserine-treated rats; (ii) dietary MaxEPA inhibits the conversion of LA to AA, as well as the conversion of AA to TXB2 or PGF(2α) in non-tumorous pancreatic tissue; (iii) the high levels of PGE2, PGF(2α), and TXB2 in pancreatic adenocarcinomas indicate a possible role for these eicosanoids in modulation of tumour growth. Chemicals/CAS: Anticarcinogenic Agents; Azaserine, 115-02-6; Carcinogens; Dietary Fats, Unsaturated; Docosahexaenoic Acids, 25167-62-8; Drug Combinations; Eicosapentaenoic Acid, 1553-41-9; Fatty Acids; Fatty Acids, Omega-3; Fish Oils; Maxepa; Prostaglandins

In the present study the effects of 0.1 or 1.0 g β-carotene/kg diet (LβC or HβC) and 1.0 mg or 2.5 mg selenium/kg diet (LSel or HSel), as well as combinations of the respective low and high concentrations of p-carotene and selenium (LMix or HMix) on the initiation/early promotion phase or on the late promotion phase of pancreatic carcinogenesis in azaserine-treated rats, were investigated using cell proliferation and volumetric data of atypical acinar cell foci (AACF) as parameters. The present results indicate chemopreventive effects of dietary selenium, dietary β-carotene and of their combination on the development of acinar pancreatic lesions induced in rats by azaserine. The inhibitory effect was most pronounced when p-carotene and/or selenium were added to the diets during the late promotion phase of the carcinogenic process, although inhibition was also observed with these compounds when they were added to the diets during the first 5 weeks of the study only (initiation/early promotion phase). Neither in the initiation/early promotion phase nor in the late promotion phase was a dose-related trend observed. The multiplicities of AACF with a diameter over 1.0 mm and of carcinomas in situ (CIS), as well as the incidence of CIS were not significantly different among the groups. However, in the late promotion experiment a dose-related decline in multiplicity could be observed in the selenium supplemented groups and in the groups receiving combinations of β-carotene and selenium. Cell proliferation in azaserine-induced AACF, as estimated by the bromodeoxyuridine (BrdU) labeling index, was significantly higher in HβC, HSel, LMix and HMix groups (initiation/early promotion phase) as well as in HβC, LSel, HSel, LMix and HMix groups (late promotion phase) than in high fat controls. From the present results it can be concluded that: (i) β-carotene and selenium have inhibitory effects on pancreatic carcinogenesis induced in rats by azaserine; (ii) the most clear effects were observed when selenium was given as such, or in combination with β-carotene during the late promotion phase; and (iii) β-carotene and selenium stimulate cell proliferation in AACF.

In the present study, the expression of the epidermal growth factor receptor (EGFR) was investigated in putative preneoplastic and neoplastic acinar cell lesions induced in the rat pancreas by azaserine, using Northern blotting, in situ hybridisation (ISH) and immunohistochemistry. EGFR protein levels were decreased in putative preneoplastic eosinophilic acinar cell lesions (atypical acinar cell nodules, AACN) in comparison with normal acinar cells of the pancreas. However, EGFR mRNA expression correlated positively with the volume of AACN in pancreatic homogenates and ISH showed equal or stronger EGFR mRNA expression in AACN than in the surrounding normal acinar cells. Neither EGFR protein nor EGFR mRNA was detected in more advanced lesions such as acinar adenocarcinomas (in situ). Moreover, EGFR protein expression showed an inverse relationship with the mitotic rate of the acinar cells. These findings suggest that down-regulation of EGFR at the protein level may abrogate negative constraints on cell growth, which may stimulate the development of putative preneoplastic AACN to more advanced lesions and, ultimately, acinar adenocarcinomas.

Using immunohistochemistry, Northern blotting and a semi-quantitative PCR technique, epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR) expression were studied in the pancreas of N-nitrosobis(2-oxopropyl)-amine (BOP)-treated hamsters. After initiation pancreatic carcinogenesis was modulated by a high fat diet or by injections with the cholecystokinin analogue caerulein. Autopsies were performed 6 and 12 months after the last injection with BOP. Immunohistochemistry revealed a weak expression of TGF-α in normal acinar cells and a stronger expression in ductular and centro-acinar cells. Overexpression of TGF-α was observed in advanced putative preneoplastic lesions (classified as borderline lesions) and in ductular adenocarcinomas. EGFR immunoreactivity was present only in ductular adenocarcinomas. EGF peptide expression was observed both in acinar and ductular normal and tumorous cells and the level of expression did not change significantly during carcinogenesis. Moreover, the post-initiation treatments did not cause differences in EGF, TGF-α or EGFR peptide or mRNA levels, except for a significantly lower expression of TGF-α mRNA in hamsters fed a high fat diet when compared with those fed a low fat diet. TGF-α mRNA levels increased, whereas EGF mRNA levels decreased significantly in total pancreatic homogenates of BOP-treated hamsters in comparison with untreated controls. Also, in ductular adenocarcinomas TGF-α and EGFR (but not EGF) mRNA levels were significantly higher than in normal pancreatic homogenates. In pancreatic homogenates obtained 6 months after the last BOP injection, these differences were less pronounced in comparison with those obtained after 12 months. The present results indicate that TGF-α (but not EGF) might act in a paracrine or autocrine manner in pancreatic tumours in BOP-treated hamsters via simultaneously expressed EGFR. However, TGF-α, EGF and EGFR do not seem to be involved in the modulating effects of a high fat diet or caerulein treatment on pancreatic carcinogenesis in BOP-treated hamsters.