Skip to main content

Advertisement

Log in

Expression and Prognostic Significance of Pepsinogen C in Gastric Carcinoma

  • Original Article
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background: In this study we evaluated the expression and clinical significance of pepsinogen C, an aspartic proteinase involved in the digestion of proteins in the stomach, in patients with gastric cancer.

Methods: Pepsinogen C expression was examined by immunohistochemical methods in a series of 95 gastric carcinomas. The prognostic value of pepsinogen C was retrospectively evaluated by multivariate analysis taking into account conventional prognostic parameters. Follow-up period of patients was 21.4 months.

Results: A total of 25 (26.3%) gastric carcinomas stained positively for pepsinogen C. The percentage of pepsinogen C-positive tumors was higher in well-differentiated (50%) than in moderately differentiated (19.5%) and poorly differentiated (21.9%) tumors (P < .05). Similarly, significant differences in pepsinogen C immunostaining were found between node-negative and node-positive tumors (47.1% vs. 14.7%; P < .001). In addition, statistical analysis revealed that pepsinogen C expression was associated with clinical outcome in gastric cancer patients. Low pepsinogen C levels predicted short overall survival periods in the overall group of patients with gastric cancer (P < .001), and in 71 patients with resectable carcinomas (P < .005). Multivariate analysis according to Cox’s model indicated that pepsinogen C immunostaining was an independent predictor of outcome for both overall and resectable gastric cancer patients (P < .05, for both).

Conclusions: The expression of pepsinogen C in gastric cancer may represent a useful biological marker able to identify subgroups of patients with different clinical outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Samloff IM. Slow moving protease and the seven pepsinogens: electrophoretic demonstration of the existence of eight proteolytic fraction in human gastric mucosa. Gastroenterology 1969;57:659–669.

    PubMed  CAS  Google Scholar 

  2. Samloff IM, Liebman WM. Cellular localization of the group II pepsinogens in human stomach and duodenum by immunofluorescence. Gastroenterology 1973;65:36–42.

    PubMed  CAS  Google Scholar 

  3. Ichinose M, Miki K, Furihata C, et al. Radioimmunoassay of serum group I and group II pepsinogens in normal controls and patients with various disorders. Clin Chim Acta 1982;126:183–191.

    PubMed  CAS  Google Scholar 

  4. Samloff IM, Varis K, Ihamaki T, Siurala M, Rotter JI. Relationship among serum pepsinogen I, serum pepsinogen II and gastric mucosal histology: a study in relatives of patient with pernicious anemia. Gastroenterology 1982;83:204–209.

    PubMed  CAS  Google Scholar 

  5. Miki K, Ichinose M, Kawamura N, et al. The significance of low serum pepsinogen levels to detect stomach cancer associated with extensive chronic gastritis in Japanese subjects. Jpn J Cancer Res 1989;80:111–114.

    PubMed  CAS  Google Scholar 

  6. Miki K, Ichinose M. Chronic atrophic gastritis and serum pepsinogen levels. Jpn J Cancer Clin 1992;38:221–229.

    Google Scholar 

  7. Nomura A, Stemmerman GN, Samloff IM. Serum pepsinogen I as a predictor of stomach cancer. Ann Intern Med 1980;93:537–540.

    PubMed  CAS  Google Scholar 

  8. Huang SC, Miki K, Furihata C, Ichinose M, Shimizu A, Oka H. Enzyme-linked immunosorbent assays for serum pepsinogens I and II using monoclonal antibodies with data on peptic ulcer and gastric cancer. Clin Chim Acta 1988;175:37–50.

    PubMed  CAS  Google Scholar 

  9. Farinati F, Holmgren J, Di Mario F, et al. CA 50 determination in body fluids: can we screen patients at risk for gastric cancer? Int J Cancer 1991;47:7–11.

    PubMed  CAS  Google Scholar 

  10. Asaka M, Kimura T, Kudo M, et al. Relationship of Helicobacter pylori to serum pepsinogens in an asymptomatic Japanese population. Gastroenterology 1992;102:760–766.

    PubMed  CAS  Google Scholar 

  11. Matsukura N, Onda M, Tokunaga A, et al. Significance of serum markers pepsinogen I and II for chronic atrophic gastritis, peptic ulcer, and gastric cancer. J Clin Gastroenterol 1993;17(Suppl 1):146–150.

    Article  Google Scholar 

  12. You WC, Blot WJ, Zhang L, et al. Serum pepsinogens in relation to precancerous gastric lesions in a population at high risk for gastric cancer. Cancer Epidemiol Biomarkers Prev 1993;2:113–117.

    PubMed  CAS  Google Scholar 

  13. Parsonnet J, Samloff IM, Nelson LM, Orentreich N, Vogelman JH, Friedman GD. Helicobacter pylori, pepsinogen, and risk for gastric adenocarcinoma. Cancer Epidemiol Biomarkers Prev 1993;2:461–466.

    PubMed  CAS  Google Scholar 

  14. Webb PM, Hengels KJ, Moller H, et al. The epidemiology of low serum pepsinogen A levels and an international association with gastric cancer rates. Gastroenterology 1994;107:1335–1344.

    PubMed  CAS  Google Scholar 

  15. Kikuchi S, Wada O, Miki K, et al. Serum pepsinogen as a new marker for gastric carcinoma among young adults. Cancer 1994;73:111–115.

    Google Scholar 

  16. Fukuda H, Saito D, Hayashi S, et al. Helicobacter pylori infection, serum pepsinogen level and gastric cancer: a case-control study in Japan. Jpn J Cancer Res 1995;86:64–71.

    PubMed  CAS  Google Scholar 

  17. Hattori Y, Tashiro H, Kawamoto T, Kodama Y. Sensitivity and specificity of mass screening for gastric cancer using the measurement of serum pepsinogens. Jpn J Cancer Res 1995;86:1210–1215.

    PubMed  CAS  Google Scholar 

  18. Kitahara F, Kobayashi K, Sato T, Kojima Y, Araki T, Fujino MA. Accuracy of screening for gastric cancer using serum pepsinogen concentrations. Gut 1999;44:693–697.

    Article  PubMed  CAS  Google Scholar 

  19. Reid WA, Valler MJ, Kay J. Aspartic proteinases in gastric carcinomas. In: Kostka V, ed. Aspartic proteinases and their inhibitors. Berlin: Walter de Gruyter, 1985:519–523.

    Google Scholar 

  20. Busby-Earle RMC, Williams ARW, Piris J. Pepsinogens in gastric carcinomas. Hum Pathol 1986;17:1031–5.

    PubMed  CAS  Google Scholar 

  21. Stemmerman GN, Samloff IM, Hayashi T. Pepsinogens I and II in carcinoma of the stomach: an immunohistochemical study. Appl Pathol 1986;3:159–163.

    Google Scholar 

  22. Fiocca R, Crinaggia M, Villani L, Capella C, Solcia E, Samloff M. Expression of pepsinogen II in gastric Cancer. Its relationship to local invasion and lymph node metastases. Cancer 1988;61:956–962.

    PubMed  CAS  Google Scholar 

  23. Konishi N, Matsumoto K, Hiasa Y, Kitahori Y, Hayashi I, Matsuda H. Tissue and serum pepsinogen I and II in gastric cancer identified using immunohistochemistry and rapid ELISA. Clin Pathol 1995;48:364–367.

    CAS  Google Scholar 

  24. Hermanek P, Sobin LH, eds. UICC TNM Classification of Malignant Tumors. 4th ed, 2nd rev. Berlin: Springer, 1992.

    Google Scholar 

  25. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal type carcinomas. An attempt at a histological classification. Acta Pathol Microbiol Scand 1965;64:31–49.

    CAS  PubMed  Google Scholar 

  26. Sánchez LM, Freije JMP, Merino AM, Vizoso F, Foltmann B, López-Otín C. Isolation and characterisation of a pepsin C zymogen produced by human breast tissues. J Biol Chem 1992;267:24725–24731.

    PubMed  Google Scholar 

  27. Vaitukaitis JL. Production antisera with small doses of immunogen: multiple intradermal injections. Methods Enzymol 1981;73:46–52.

    Article  PubMed  CAS  Google Scholar 

  28. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481.

    Google Scholar 

  29. Mantel N, Myers M. Problems of convergence of maximum likelihood iterative procedures in multiparameter situations. J Am Statis Assoc 1971;66:484–491.

    Google Scholar 

  30. Cox DR. Regression models and life tables. J R Stat Soc 1972;B34:187–220.

    Google Scholar 

  31. Dixon WJ, ed. BMDP Statistical Software. Berkeley: University of California Press, 1986.

    Google Scholar 

  32. Vizoso F, Sánchez LM, Díaz-Itza I, Merino AM, López-Otín C. Pepsinogen C is a new prognostic marker in primary breast cancer. J Clin Oncol 1995;13:54–61.

    PubMed  CAS  Google Scholar 

  33. Serra C, Vizoso F, Rodríguez JC, et al. Expression of pepsinogen C in gynecomastias and male breast carcinomas. World J Surg 1999;23:439–445.

    Google Scholar 

  34. Tenti P, Aguzzi A, Riva C, et al. Ovarian mucinous tumors frequently express markers of gastric, intestinal, and pancreatobiliary epithelial cells. Cancer 1992;69:2131–2142.

    PubMed  CAS  Google Scholar 

  35. Tenti P, Romagnoli S, Silini E, Zappatore R, Giunta P, Stella G, Carnevali L. Cervical adenocarcinoma express markers common to gastric, intestinal, and pancreatobiliary epithelial cells. Pathol Res Pract 1994;190:342–349.

    PubMed  CAS  Google Scholar 

  36. Konishi N, Nakaoka S, Matsumoto K, et al. Expression of pepsinogen II with androgen and estrogen receptors in human prostate carcinoma. Pathol Int 1999;49:203–207.

    PubMed  CAS  Google Scholar 

  37. Ichinose M, Miki K, Wong NS, et al. Methylation and expression of human pepsinogen genes in normal tissues and their alteration in stomach cancer. Jpn J Cancer Res 1991;82:686–692.

    PubMed  CAS  Google Scholar 

  38. Watanabe M, Higashi M, Hashimoto M. Elevation of tissue cathepsin B and L activities in gastric cancer. Hepatogastroenterol 1987;34:120–122.

    CAS  Google Scholar 

  39. Watanabe M, Higashi M, Watanabe A. Cathepsin B and L activities in gastric cancer tissue: correlation with histological findings. Biochem Med Biol 1989;42:21–29.

    CAS  Google Scholar 

  40. Matsuo K, Kobayashi I, Tsukuba T, et al. Immunohistochemical localization of cathepsins D and E in human gastric cancer: a possible correlation with local invasive and metastatic activities of carcinoma cells. Human Pathol 1996;27:184–190.

    CAS  Google Scholar 

  41. Saku T, Sakai H, Tsuda N, Okabe H, Kato Y, Yamamoto K. Cathepsin D and E in normal, metaplastic, dysplastic, and carcinomatous gastric tissue: an immunohistochemical study. Gut 1990;31:1250–1255.

    PubMed  CAS  Google Scholar 

  42. Azuma T, Liu WG, Van der Laan DJ, Bowcock AM, Taggart RT. Human gastric cathepsin E gene. Multiple transcripts result from alternative polyadenylation of the primary transcripts of a single gene locus at 1q31–q32. J Biol Chem 1992;267:1609–1614.

    PubMed  CAS  Google Scholar 

  43. Heiss MM, Babic R, Allgayer H, et al. Tumor-associated proteolysis and prognosis: New functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol 1995;13:2084–2093.

    PubMed  CAS  Google Scholar 

  44. Ito H, Yonemura Y, Fujita H, et al. Prognosis relevance of urokinase- type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in gastric cancer. Virchows Arch 1996;427:487–496.

    PubMed  CAS  Google Scholar 

  45. Maeda K, Chung YS, Sawada T, et al. Combined evaluation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2 expression in gastric carcinoma. Int J Ocology 1996;8:499–503.

    Google Scholar 

  46. Gottesman M. The role of proteases in cancer. Semin Cancer Biol 1990;1:97–160.

    Google Scholar 

  47. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991;64:327–336.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernández, R., Vizoso, F., Rodríguez, J.C. et al. Expression and Prognostic Significance of Pepsinogen C in Gastric Carcinoma. Ann Surg Oncol 7, 508–514 (2000). https://doi.org/10.1007/s10434-000-0508-9

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10434-000-0508-9

Key Words

Navigation