CORRESPONDENCE

Re: Etiology of Pancreatic Cancer, With a Hypothesis Concerning the Role of N-Nitroso Compounds and Excess Gastric Acidity

Gabriele Capurso, Gianfranco Delle Fave, Nick Lemoine

Affiliations of authors: Cancer Research UK Molecular Oncology Unit, Imperial College London Faculty of Medicine at Hammersmith Campus, London, U.K. (GC, NL); Digestive and Liver Disease Unit, II Medical School, University "La Sapienza," Rome, Italy (GC, GDF).

Correspondence to: Gabriele Capurso, MD, Cancer Research UK Molecular Oncology Unit, Imperial College London Faculty of Medicine at Hammersmith Campus, Du Cane Rd., W12 0NN London, U.K. (e-mail: gabriele.capurso{at}cancer.org.uk)

We read with great interest the exhaustive review from Risch (1), which focused on the possible role of gastric acid hypersecretion in the etiology of pancreatic cancer. The author presented several strands of evidence connecting alterations of gastric physiology in the course of Helicobacter pylori infection with pancreatic cancer. It is hypothesized that the decrease in somatostatin release by gastric delta cells in H. pylori–infected patients may increase the secretion of secretin from S cells in the duodenum and jejunum that, in turn, may favor carcinogenesis through its trophic effect on pancreatic duct epithelium. This view is supported by the fact that gastric acid hypersecretion, like that observed in most duodenal ulcer patients, causes increased bicarbonate secretion from the pancreas by increased secretin release.

Although we agree with the rationale of the hypothesis, we think that some points remain at least controversial, and additional observations may help to clarify the previously reported (2) possible link between H. pylori infection and pancreatic cancer.

The first point of doubt about the relationship between increased gastric acid secretion and pancreatic cancer arises from the fact that most of the studies cited by Risch (1) that report an increased risk of pancreatic cancer involve patients who underwent gastric surgery for duodenal ulcers. These subjects will have decreased acid secretion after gastrectomy and, when pancreatic cancer has subsequently developed, it has typically been decades after gastrectomy. To further confound the hypothesis, although some have reported an epidemiologic association between duodenal ulcers and pancreatic cancer, others have suggested that pernicious anemia is a risk factor for the development of pancreatic cancer (3). Moreover, although decreased concentrations of somatostatin are observed in the gastric antral mucosa of patients with H. pylori infection (as pointed out by Risch), the density of delta cells is reduced more in patients with pernicious anemia than in patients with duodenal ulcers (4).

Pernicious anemia represents the clinical end stage of atrophic body gastritis which, in most cases, is linked to H. pylori infection and is characterized by hypochlorhydria or achlorhydria, being the exact opposite of duodenal ulcers in terms of pathophysiologic consequences of H. pylori infection. What eventually links duodenal ulcers and pernicious anemia, apart from H. pylori infection, is hypergastrinemia caused by the infection impairing the acid-mediated inhibitory control of gastrin release in the former and by negative feedback as a consequence of the reduction of gastric acid secretion by parietal cells in the latter.

It is therefore tempting to speculate that hypergastrinemia itself may be the link between gastric pathology and pancreatic cancer. Hypergastrinemia can indeed play a role in the development of various digestive malignancies (5). Gastrin has been shown to increase the growth of human pancreatic cancer cells in culture, and both gastrin and its receptor are expressed by pancreatic cancer cells, thus supporting recent use of anti-gastrin antibodies in pancreatic cancer patients (6).

Finally, another plausible link between gastritis and pancreatic cancer may be represented by the decreased plasma concentration of a spectrum of antioxidant compounds observed in patients with H. pylori gastritis (7), particularly ascorbic acid, which decreases the risk of developing various neoplasms including pancreatic cancer.

In conclusion, although we agree that altered gastric physiology may have an impact on cell proliferation and the subsequent risk of carcinogenesis in other organs, we believe that hypotheses other than those presented by Risch may be reasonably considered for the increased risk of pancreatic cancer in H. pylori–infected subjects.

REFERENCES

1 Risch HA. Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity. J Natl Cancer Inst 2003;95:948–60.[Abstract/Free Full Text]

2 Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, Perez-Perez G, Taylor PR, Virtamo J, et al. ATBC Study. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. J Natl Cancer Inst 2001;93:937–41.[Abstract/Free Full Text]

3 Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev 2003;27:87–93.[CrossRef][ISI][Medline]

4 Arnold R, Hulst MV, Neuhof CH, Schwarting H, Becker HD, Creutzfeldt W. Antral gastrin-producing G-cells and somatostatin-producing D-cells in different states of gastric acid secretion. Gut 1982;23:285–91.[Abstract]

5 Jensen RT. Involvement of cholecystokinin/gastrin-related peptides and their receptors in clinical gastrointestinal disorders. Pharmacol Toxicol 2002;91:333–50.[CrossRef][ISI][Medline]

6 Brett BT, Smith SC, Bouvier CV, Michaeli D, Hochhauser D, Davidson BR, et al. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol 2002;20:4225–31.[Abstract/Free Full Text]

7 Annibale B, Capurso G, Delle Fave G. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Dig Liver Dis 2002;34 Suppl 2:S72–7.[CrossRef][ISI][Medline]



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