Correspondence to: Harvey A. Risch, M.D., Ph.D., Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College St., P.O. Box 208034, New Haven, CT 065208034 (e-mail: harvey.risch{at}yale.edu).
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ABSTRACT |
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INTRODUCTION |
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I propose that, in humans, risk of pancreatic cancer is increased by long-term conditions of excess gastric/duodenal acidity and by frequent or repeated gastrointestinal or other exposures to N-nitroso compounds or their precursors. The excess acidity, largely asymptomatic for most individuals, is typically associated with chronic basal stimulation of pancreatic bicarbonate production, whichthrough a trophic effect of secretin, bicarbonates principal hormonal secretagoguemay be associated with pancreatic ductular hyperplasia and increased DNA synthesis (11). With respiratory or gastrointestinal intake or formation of N-nitroso xenobiotics, the pancreatic ductular epithelium is exposed to carcinogens through the circulation (12). The ductular epithelium can metabolically activate the carcinogens (13), if activation has not already occurred in the liver. Metabolically activated N-nitroso carcinogens induce DNA adducts and single-strand breaks (14) and appear to stimulate DNA synthesis in the pancreatic ductular epithelium (15). Chronic secretin stimulation and N-nitroso compound exposures potentially overwhelm DNA repair capabilities, acting synergistically to induce tumor development (16). Thus, the majority of this review focuses on gastric/duodenal acidity and other factors potentially affecting chronic basal pancreatic ductular bicarbonate secretion, and on factors bearing on ductular epithelial exposures to N-nitroso carcinogens.
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GENERAL CONSIDERATIONS |
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In the United States, more than 90% of malignant pancreatic neoplasms are classified as ductal adenocarcinomas (3,21), yet ductal or ductular epithelial cells constitute only about 4% of the human exocrine pancreas (17). Although acini account for 80% of the organ parenchyma (22), acinar cell carcinomas are rare (3,21). In spite of the histologic and ultrastructural resemblance of ductal carcinoma cells to the cuboidal, mucus-producing cells of the normal ductular epithelium (23), there is some controversy about the true cellular origin of these neoplasms. Ductular and acinar cells are histogenetically derived from a common precursor cell that is essentially indistinguishable from duct epithelial cells by light or electron microscopy (24). Ductal adenocarcinomas in hamster pancreata treated with N-nitroso carcinogens have been suggested to arise from acinar cells that have undergone dedifferentiation, with loss of both rough endoplasmic reticulum and zymogen granules, the characteristic features of acini (25). Development of pseudoductules derived from dedifferentiated acinar cells may occur with longer carcinogen exposures (25). However, evidence favoring a ductule epithelial cell origin of ductal adenocarcinomas appears more convincing. Under normal differentiation, the two cell types develop distinct antigens that are detected by monoclonal antibodies, AC-1 against acinar cells and HP-DU-1 against ductal epithelium (24). In cultured human pancreatic explant cells, N-nitroso carcinogen exposures (N-nitrosodimethylamine [NDMA], see "Human N-Nitroso Compound Exposures" section, below), which are known to produce ductal carcinomas in the explant model, show carcinogen uptake only in normal precursor cells labeled by HP-DU-1 (24). In addition, ductal adenocarcinomas consistently express carcinoembryonic antigen, CA 19-9, DU-PAN-2, and other antigens that are detectable in normal duct epithelium (22) and that are associated with the degree of ductal epithelial atypia (26,27). In the hamster model, a blood group A-like antigen is detectable on the luminal surface of normal pancreatic ductal and ductular cells but not on acinar epithelium. With N-nitrosamine exposures [e.g., N-nitrosobis(2-oxopropyl)amine (BOP), see "Human N-Nitroso Compound Exposures" section, below], this antigen is highly expressed on hyperplastic and neoplastic ductal and ductular cells (28). Furthermore, in N-nitrosamine-treated hamsters, secretory abnormalities involve only pancreatic ductular fluid and bicarbonate output and not acinar protein production; these abnormalities antedate tumor appearance and are not caused by tumor obstruction (29). Finally, human ductal adenocarcinomas express the same set of intermediate filaments, villin and keratins 7, 8, 18, and 19, as normal pancreatic ductal epithelium, whereas acinar cells usually express neither villin nor keratins 7 or 19 (22). Thus, the evidence seems to favor pancreatic ductal adenocarcinomas as arising from the ductular epithelial lining.
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ANIMAL AND HUMAN EXPLANT CELL MODELS OF PANCREATIC ADENOCARCINOMA |
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HUMAN N-NITROSO COMPOUND EXPOSURES |
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It has been observed that workers employed in the manufacturing of cured rubber products are also exposed to N-nitrosamines. In some plants in the United States (38) and France (44), among various N-nitrosamines, NDMA was detected at the highest levels or was the one most frequently encountered, whereas at other plants in the United States (45) and in Germany (46), N-nitrosomorpholine (NMOR) appeared to predominate and NDMA occurred at lower levels. In a study of two industrial rubber plants where appreciable concentrations of atmospheric NDMA were detected, the frequencies of N7- and possibly O6-methyldeoxyguanine (mdG) DNA adducts in peripheral blood leukocytes appeared to be associated with exposure category levels (47). In the categories of highest exposure to NDMA, average concentrations of N7-mdG adducts were approximately 3.7 adducts per 107 guanine bases (47). This adduct concentration is approximately 200-fold lower than that required for the induction of neoplasia in the short-term HPOP hamster model (15) and is comparable with peripheral blood leukocyte adduct concentrations measured in nonsmokers (3.4 adducts per 107 guanine bases) with the same 32P-postlabeling high-pressure liquid chromatography methods (48). The similar adduct levels between normal nonsmokers and highly N-nitrosamine-exposed rubber workers may explain why the latter were apparently not found to have an increased risk of pancreatic cancer (46). Adduct concentrations in smokers are approximately double those of nonsmokers (48), suggesting that very long-term occupational exposures to appreciably greater N-nitrosamine levels would be required to detect an increased risk.
Aside from tobacco usage, the main route of human exposure to N-nitroso compounds is ingestion from dietary sources. Preformed N-nitrosamines and endogenously generated N-nitrosamines and N-nitrosamides may contribute to this exposure. N-Nitrosamines (primarily NDMA) form in protein-containing foods dried at high temperatures (beer ingredients, nonfat dry milk, cooked bacon, or dried meats) or preserved with nitrite (cured, smoked, or pickled meats and fish) (39,40,49). Estimates of the average daily dietary intake of exogenous N-nitrosamines in western diets range from 0.2 to 1.0 µg/day (39,40). N-Nitrosamides, short-lived compounds that do not persist in foods, are formed in the stomach from nitrite and ingested amides, such as creatinine, in foods of animal origin (50,51). Formation of endogenous N-nitroso compounds is thought to be proportional to the amine or amide concentration, which is in excess, and to the square of the nitrite concentration (49). Total N-nitroso compound exposures from smoked or processed meats are derived at least as much from their nitrites as from their N-nitrosamines. It has also been suggested that approximately 25% of ingested nitrate is recirculated into the saliva and that 20% of salivary nitrate is reduced to nitrite, yielding a conversion of 5% of exogenous nitrate to endogenous nitrite (49,50,52). According to this theory, most human nitrite exposure would be from the consumption of vegetables common in the diet. However, for gastric cancer, which is most likely related to nitrite exposure, empirical evidence relates exogenous nitrite intake to increased risk (53,54), whereas nitrate intake (mostly from vegetables) is associated with decreased risk (53). Large amounts of nitrate and protein are required to increase endogenous N-nitrosamine formation (42,43), suggesting that nitrate intake from vegetables is not particularly important for nitrite-related risk effects. Perhaps by the time that gastrointestinal nitrate absorption, salivary recirculation, and conversion to nitrite has occurred, protein or amides in the gastric contents have left the stomach and are no longer available for N-nitrosation. In any event, determining the intake of nitrite (and possibly exogenous N-nitrosamines) is likely the most relevant method for assessing human dietary exposures to N-nitroso compounds.
Finally, N-nitrosamines (mainly, N-nitrosodiethylamine [NDEA] and NDMA) or N-nitroso compounds in general are present and measurable in the gastric juice of subjects after overnight fasting (41,55). This basal endogenous formation occurs through acid-catalyzed N-nitrosation at gastric conditions below pH 2.5 and through bacterially catalyzed N-nitrosation, to an increasing degree, as gastric pH increases from 5 to 8 (41,55). Exposure levels from basal endogenous N-nitroso compounds appear to be an order of magnitude lower than those from typical dietary sources (3941,55).
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PANCREATIC CANCER AND EXPOSURE TO DIETARY N-NITROSO COMPOUNDS |
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CONTROL OF GASTRIC ACIDITY |
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Upper gastrointestinal and pancreatic function is controlled by many interacting hormones and modulated by neuroendocrine processes. The simplifications provided below do some injustice to the complexity of gastrointestinal physiology but help to identify physiologic mechanisms through which risk factors for pancreatic cancer could operate. To start with, three principal hormones are involved in gastric acid (i.e., HCl) regulation: gastrin, somatostatin, and secretin (Table 2). These hormones exist in a number of precursor and mature polypeptide forms, variants that are beyond the scope of this review.
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During the gastric phase, food in the stomach (primarily proteins) strongly buffers the released acid, which is secreted at near-maximal rates (19). As gastric emptying progresses, the moderately acidic chyme in the antrum and duodenum stimulates the secretion of somatostatin from D cells of the antrum and secretin from S cells of the duodenum and proximal jejunum (73). The somatostatin turns off the release of gastrin from nearby antral G cells and inhibits the histamine secretion of the ECL cells by an endocrine route (73). The net effect is to return parietal cell acid secretion to basal levels. The secretin released by duodenal and jejunal S cells travels through the circulation to the pancreatic ductal epithelium, where it stimulates the production of fluid and bicarbonate. Postprandial plasma levels of secretin in humans tend to be low but still functionally important for ductal bicarbonate production (7779), although CCK and neuropeptide factors have been suggested as potentiators of the secretin effect (19). Nevertheless, there is no doubt that gastric acid drives pancreatic bicarbonate secretion (19,78). The bicarbonate, entering the gut through the papilla of Vater, progressively neutralizes the acidic chyme as it travels distally through the duodenum, with a steep pH gradient, typically from pH 2.03.5 in the first few centimeters to pH 5.06.0 in the mid-duodenum (19,80). Hepatic bicarbonate may also participate in the neutralization (81).
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EXCESS GASTRIC/DUODENAL ACIDITY AND PANCREATIC CANCER |
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HELICOBACTER PYLORI AND GASTRIC/DUODENAL ACIDITY |
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Many mechanisms have been proposed for how H. pylori induces duodenal or gastric ulcers. Mechanisms for duodenal ulcers generally involve H. pylori-related hypergastrinemia or increased sensitivity to gastrin and consequent hyperacidity (121). The hyperacidity leads to duodenal gastric metaplasia and colonization of the duodenum by H. pylori, mucosal inflammation, loss of duodenal mucosal bicarbonate, and ulceration (120). Interleukin 1 (IL-1
) and other inflammatory cytokines are involved in the inflammatory process (120). In general, H. pylori flourishes on the surface of non-acid-secreting gut epithelium, particularly the gastric antrum, colonizes the corpus only when acid production there is inadequate or suppressed (122,123), and is lost from the corpus with progressive atrophy and other preneoplastic changes (124). Colonization of the antrum by H. pylori has little effect on the number of G cells but involves specific reductions in the number and function of antral D cells (125136), possibly mediated by luminal ammonia produced by the organism (125). Somatostatin levels in the antral mucosa are decreased because of a reduction in the number of D cells, but synthesis of somatostatin mRNA per D cell is also reduced (126,130). The suppression of somatostatin may also disinhibit ECL cell histamine secretion (137,138). Thus, the net effects of antral H. pylori colonization are paracrine disinhibition of antral G-cell function, hypergastrinemia, and hyperacidity. The suppression of antral D cells is observed in normal, asymptomatic H. pylori carriers (127,130,131), not just in carriers with duodenal ulcers or non-ulcer dyspepsia. Asymptomatic H. pylori carriers have higher basal and postprandial plasma gastrin levels than normal individuals (130,139).
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H. PYLORI, DUODENAL ULCERS, SECRETIN, AND BICARBONATE |
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SECRETIN (OR BICARBONATE) AND PANCREATIC CANCER |
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Parenthetically, a similar mechanism of pancreatic neoplasia, involving N-nitrosamine exposures along with excessive CCK stimulation, has been proposed (150). CCK is a stimulator of pancreatic growth and protein and DNA synthesis (147,149, 151), with a major trophic effect in the acini (145,152,153). Dietary proteases, found in raw soy flour and fermented raw soybeans (but not heat-treated flour or beans), strongly increase CCK secretion and its pancreatic stimulation (154) and, in large doses, induce murine pancreatic adenomas and invasive cancers (155). However, there is little empirical evidence from humans to support this hypothesis. Raw soy products or other foods containing dietary proteases constitute a minuscule fraction of the normal western diet. One study that examined fasting serum CCK levels failed to detect a difference between case patients with pancreatic cancer and control subjects (156). Finally, it is unclear whether factors that exert their primary physiologic effects on pancreatic acini are relevant for adenocarcinomas arising from the ductular epithelium.
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H. PYLORI AND PANCREATIC CANCER |
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Although H. pylori does appear to colonize the bile ducts and may be responsible for a proportion of malignant biliary tract disease (159,160), there is no evidence for direct pancreatic colonization by the organism. The study in Austria (157) obtained tumor and surrounding normal tissue specimens from 20 case patients and observed no bacteria in any of the malignant tissue or in any adjacent normal pancreatic ducts. Researchers in a study in Sweden identified Helicobacter genus-specific DNA in five of six pancreatic ductal adenocarcinoma biopsy specimens but, with H. pylori-specific primers in the polymerase chain reaction assays, detected no H. pylori (160). Two normal pancreatic tissue biopsy specimens were negative for Helicobacter by genus-specific polymerase chain reaction primers (160). Pancreatic juice exerts some antibacterial activity (161) and may limit the ability of H. pylori to colonize the pancreas.
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MODULATION OF GASTRIC ACIDITY BY INFLAMMATORY CYTOKINES |
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OTHER RECENT HYPOTHESES ON THE ETIOLOGY OF PANCREATIC CANCER |
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An interesting review (173) proposed that various aspects of the epidemiology of pancreatic cancer might be explained by long-term exposure to cadmium, which accumulates in the pancreas. Risk factors for pancreatic cancer, related to cadmium exposure, include cigarette smoking and work in certain occupations or industries involving metal welding or soldering, pesticides, paints, or batteries (173). Schwartz and Reis (173) suggested that molecular substitution of cadmium for zinc might underlie its carcinogenic mechanism. In rodent models, cadmium is both mitogenic and carcinogenic to the pancreas but apparently not to the ductular epithelium per se (174,175). Cadmium accumulation in the human renal cortex is approximately 30 times that in the human pancreas (176,177), although in animal models, administration of cadmium does not cause kidney tumors (175). It is perhaps most relevant for this review that cadmium appears to potentiate the effect of secretin on the volume of pancreatic fluid output (178), without involving CCK (178). Although dietary sources of cadmium such as shellfish, cereals, roots, and tubers are common (179), cigarette smoking may be a more important source, even in areas with high cadmium contamination (180). Absorption and metabolism of dietary cadmium may be strongly affected by intake of zinc (181) or fiber (182). Aside from cigarette smoking, occupational sources may provide nontrivial exposures to cadmium [for review, see (173)]. However, a meta-analysis of occupational studies examining cadmium exposures did not find an increased risk of pancreatic cancer (183).
Pyrolysis Carcinogens
Cooking at high temperature or incomplete burning of organic materials produces low but measurable levels of mutagenic heterocyclic amines and PAHs that may be carcinogenic to the pancreas and other organs. Heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine are typically found in pan-fried, grilled, or barbecued meats and fish, particularly when cooked to "very well done," and in gravies made with pan drippings from such foods (184). Various heterocyclic amines are also found in mainstream and sidestream tobacco smoke and in diesel exhaust particulates (185). PAHs are typically found in tobacco smoke, automotive exhausts, and smoke from the burning of coal tar (186). Although heterocyclic amines and PAHs are generally mutagenic and can produce DNA adducts in the pancreas, they do not produce ductal tumors by themselves and thus are not pancreatic carcinogens per se (187). Two heterocyclic amines (3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole [Trp-P-1] and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [4,8-DiMeIQx]) are promoters for hamster pancreatic ductal adenocarcinoma after BOP administration (see Table 1); however, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and various other heterocyclic amines are not promoters with BOP (188). There is little evidence that exposure to these substances increases risk of pancreatic cancer in humans. Trp-P-1 and related heterocyclic amines are inactivated by nitrite, under mildly acidic conditions and nitrite concentrations that are generally seen in saliva and in the stomach (189). In a meta-analysis (183), occupational exposures to diesel exhausts and to PAHs were not associated with statistically significant increased risks. A recent casecontrol study of meat intake, cooking methods, and pancreatic cancer suggested that risk was elevated for frequent consumption of grilled or barbecued red meat and possibly for fried red meat (190). This study, however, lumped together consumption of beef steak and ground beef; ground beef appears to yield almost no heterocyclic amines when grilled, barbecued, or fried to rare, medium, or well done (184). Finally, in another casecontrol study, no statistically significant risk associations were observed for functional germline polymorphisms in phase I enzymes that metabolize heterocyclic amines and PAHs to their active forms (191).
Folate
Folate deficiency may affect the risk of developing pancreatic cancer. Two studies have examined dietary intake (192) and serum levels (193) of folate in male smokers within the ATBC prospective cohort study. Both dietary and serum folate, measured at study baseline, were associated with statistically significant, decreasing trends in risk of subsequent pancreatic cancer. Use of folate vitamin supplements was not associated with risk, however (192). Two previous casecontrol studies have examined folate intake and the risk of pancreatic cancer, with conflicting results: a study in Australia did show a statistically significant trend of decreasing risk with increasing folate intake (59), but a larger study in the United States found no association (57). Low-folate diets may result in impaired acinar cellular DNA synthesis, although amylase secretion is not usually reduced (194). Because fruits and vegetables are the major dietary source of folate, it is not clear whether the reduced risks observed for dietary or serum folate result from the folate itself or from some other component of these foods. Most studies of diet and pancreatic cancer have detected a decreased risk with the consumption of fruits and vegetables (56,57,59,61,6367,70, 94,195).
Lycopene
Higher lycopene intake may be associated with a reduced risk of pancreatic cancer. A recent casecontrol study found that plasma levels of lycopene were statistically significantly lower in case patients with pancreatic cancer than in matched control subjects (196). Stronger evidence comes from the Washington County, MD, Cohort Study that found, in subjects followed for almost 15 years, statistically significantly lower baseline serum levels of lycopene in case patients with pancreatic cancer than in matched cohort control subjects (197,198). Dietary lycopene is also found in fruits and vegetables, particularly tomatoes and tomato products. Lower serum lycopene levels have been seen in individuals with certain chronic inflammatory conditions, suggesting that lycopene intake reduces the presence, extent, or degree of the inflammation or that lycopene is depleted by the inflammatory process (199). No studies to date have analyzed lycopene intake and risk of pancreatic cancer.
Glucose Intolerance and Diabetes Mellitus
The association between adult-onset diabetes mellitus (type 2 or non-insulin dependent) and risk of pancreatic cancer has been known but controversial for some time [(102); for review, see (200)]. Many of the studies have involved self-reporting of diabetes history by case and control subjects. The controversy arises because of difficulty in determining whether pancreatic cancer in its prediagnostic phase could suppress or damage pancreatic islet cells or whether the diabetes could induce or promote development of the cancer. Most likely, both mechanisms are operative. Two cohort studies have observed statistically significantly increased risks of pancreatic cancer associated with a history of diabetes at baseline of follow-up (201,202). A third study screened 35 658 male and female employees at baseline for postload plasma glucose level and then followed them for more than 25 years for mortality from pancreatic cancer (203). A statistically significant, direct trend in risk according to postload glucose level was observed; in addition, subjects self-reporting at baseline a history of diabetes were also found to be at statistically significantly higher risk. Excluding cases diagnosed within 5 years of baseline did not alter the findings. Obesity and lack of regular physical activity, which are involved in the development of diabetes, have also been associated with an increased risk of pancreatic cancer in cohort studies (201,204). Factors associated with abnormal glucose metabolism may thus play a role in the development of pancreatic cancer (203). A commentary on Gapstur et al. (203) suggested that elevated insulin levels might be acting as a growth promoter for pancreatic cancer (205). This idea could be substantiated by studies evaluating dietary glycemic index (206) and risk of pancreatic cancer. A very recent cohort study indeed observed increased risk according to an index of glycemic load (207), although the result was of borderline statistical significance. In addition, it has been seen in animal experiments that euglycemic hyperinsulinemic clamp strongly reduces the effect of secretin on pancreatic fluid and bicarbonate output (208,209). Adult-onset diabetes mellitus is characterized by long-term insulin insensitivity caused by decreased insulin-receptor concentrations and activity, and ultimately by
-cell exhaustion and lack of insulin production (210). These observations are consistent with the hypothesized secretin mechanisms and could also explain the risk association with diabetes mellitus.
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CONCLUSION |
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Manuscript received November 1, 2002; revised April 23, 2003; accepted May 1, 2003.
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