Skip to main content

Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy

Abstract

Background and aims

Overexpression of p53 protein in malignancies induces an immune response in some cancer patients. We investigated whether production of serum antibodies against p53 (p53-Ab) is associated with pathohistological parameters of colorectal carcinoma and whether p53-Ab can serve as a tumor marker during cancer treatment.

Patients and methods

Serum samples from 220 colorectal cancer patients during surgery and adjuvant chemotherapy and 42 healthy controls were tested for the presence of p53-Ab by ELISA. Expression of p53 protein in tumors was determined using mouse anti-human p53-Ab.

Results

Serum p53-Ab were detected in 18% of patients while all controls were negative. A strong correlation between p53-Ab production and p53 protein expression was observed: 70% of p53-Ab positive cases had tumors positive for p53 vs. 52% of p53-Ab negative cases. There was also a significant predominance of p53-Ab positive cases in Dukes’ stages B and C over stage A. Although surgery alone reduced p53-Ab levels, decreases in p53-Ab titer became significant midterm through chemotherapy compared to both pre- and postoperative values and remained decreased until the completion of treatment.

Conclusion

The presence of p53-Ab in sera of patients with colorectal cancer indicates tumors in more advanced histopathologic stages (Dukes’ B, C). Due to low sensitivity (18%) p53-Ab are not recommendable as a preoperative marker for colorectal cancer. However, due to high specificity (100%), their monitoring after surgery and adjuvant chemotherapy has potential for early diagnosis of tumor relapse in p53-Ab positive cases.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Soussi T, Legros Y, Lubin R, Ory K, Schlichtholz B (1994) Multifactorial analysis of p53 alteration in human cancer: a review. Int J Cancer 57:1–9

    CAS  Google Scholar 

  2. 2.

    Kaelin WG Jr (1999) The emerging p53 gene family. J Natl Cancer Inst 91:594–598

    Google Scholar 

  3. 3.

    Scott N, Sagar P, Stewart J, Blair GE, Dixon MF, Quirke P (1991) p53 in colorectal cancer: clinicopathological correlation and prognostic significance. Br J Cancer 63:317–319

    CAS  PubMed  Google Scholar 

  4. 4.

    Flamini G, Curigliano G, Ratto C, Astone A, Ferretti G, Nucera P et al (1996) Prognostic significance of cytoplasmic p53 overexpression in colorectal cancer. An immunohistochemical analysis. Eur J Cancer 32A:802–806

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Kastrinakis WV, Ramchurren N, Rieger KM, Hess DT, Loda M, Steele G et al (1995) Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression. Oncogene 11:647–652

    CAS  PubMed  Google Scholar 

  6. 6.

    Poller DN, Baxter KJ, Shepherd NA (1997) p53 and Rb1 protein expression: are they prognostically useful in colorectal cancer? Br J Cancer 75:87–93

    CAS  PubMed  Google Scholar 

  7. 7.

    Kressner U, Inganas M, Byding S, Blikstad I, Pahlman L, Glimelius B et al (1999) Prognostic value of p53 genetic changes in colorectal cancer. J Clin Oncol 17:593–599

    CAS  Google Scholar 

  8. 8.

    Forslund A, Kressner U, Lonnroth C, Andersson M, Lindmark G, Lundholm K (2002) P53 mutations in colorectal cancer assessed in both genomic DNA and cDNA as compared to the presence of p53 LOH. Int J Oncol 21:409–415

    CAS  PubMed  Google Scholar 

  9. 9.

    Angelopoulou K, Diamandis EP, Sutherland DJ, Kellen JA, Bunting PS (1994) Prevalence of serum antibodies against the p53 tumor suppressor gene protein in various cancers. Int J Cancer 58:480–487

    CAS  Google Scholar 

  10. 10.

    Lubin R, Schlichtholz B, Teillaud JL, Garay E, Bussel A, Wild CP (1995) p53 antibodies in patients with various types of cancer: assay, identification, and characterization. Clin Cancer Res 1:1463–1469

    CAS  Google Scholar 

  11. 11.

    Tang R, Ko MC, Wang JY, Changchien CR, Chen HH, Chen JS et al (2001) Humoral response to p53 in human colorectal tumors: a prospective study of 1:209 patients. Int J Cancer 94:859–863

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Angelopoulou K, Stratis M, Diamandis EP (1997) Humoral immune response against p53 protein in patients with colorectal carcinoma. Int J Cancer 70:46–51

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Coomber D, Hawkins NJ, Clark M, Meagher A, Ward RL (1996) Characterisation and clinicopathological correlates of serum anti-p53 antibodies in breast and colon cancer. J Cancer Res Clin Oncol 122:757–762

    Google Scholar 

  14. 14.

    Houbiers JG, van der Burg SH, van de Watering LM, Tollenaar RA, Brand A, van de Velde CJ et al (1995) Antibodies against p53 are associated with poor prognosis of colorectal cancer. Br J Cancer 72:637–641

    CAS  Google Scholar 

  15. 15.

    Kressner U, Glimelius B, Bergstrom R, Pahlman L, Larsson A, Lindmark G (1998) Increased serum p53 antibody levels indicate poor prognosis in patients with colorectal cancer. Br J Cancer 77:1848–1851

    CAS  PubMed  Google Scholar 

  16. 16.

    Hammel P, Leroy-Viard K, Chaumette MT, Villaudy J, Falzone MC, Rouillard D et al (1999) Correlations between p53-protein accumulation, serum antibodies and gene mutation in colorectal cancer. Int J Cancer 81:712–718

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Coomber DW, Hawkins NJ, Clark MA, Ward RL (1999) Generation of anti-p53 Fab fragments from individuals with colorectal cancer using phage display. J Immunol 163:2276–2283

    CAS  PubMed  Google Scholar 

  18. 18.

    Hammel P, Boissier B, Chaumette MT, Piedbois P, Rotman N, Kouyoumdjian JC et al (1997) Detection and monitoring of serum p53 antibodies in patients with colorectal cancer. Gut 40:356–361

    CAS  PubMed  Google Scholar 

  19. 19.

    Broll R, Duchrow M, Oevermann E, Wellm C, Schwandner O, Schimmelpenning H et al (2001) p53 autoantibodies in sera of patients with a colorectal cancer and their association to p53 protein concentration and p53 immunohistochemistry in tumor tissue. Int J Colorectal Dis 16:22–27

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Takeda A, Shimada H, Nakajima K, Imaseki H, Suzuki T, Asano T et al (2001) Monitoring of p53 autoantibodies after resection of colorectal cancer: relationship to operative curability. Eur J Surg 167:50–53

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Lukač J, Kusić Z, Kovačević D, Soldić Ž, Troskot B (1995) Neutrophil and monocyte phagocytic functions in patients with colorectal adenocarcinoma during fluorouracil therapy. Anticancer Res 15 (6B):2805–2809

    CAS  PubMed  Google Scholar 

  22. 22.

    Tenaud C, Negoescu A, Labat-Moleur F, Legros Y, Soussi T, Brambilla E (1994) p53 immunolabeling in archival paraffin-embedded tissues: optimal protocol based on microwave heating for eight antibodies on lung carcinomas. Mod Pathol 7:853–859

    CAS  PubMed  Google Scholar 

  23. 23.

    Walsh SV, Loda M, Torres CM, Antonioli D, Odze RD (1999) P53 and beta catenin expression in chronic ulcerative colitis-associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study. Am J Surg Pathol 23:963–969

    Article  CAS  Google Scholar 

  24. 24.

    Eguchi K, Yao T, Konomoto T, Hayashi K, Fujishima M, Tsuneyoshi M (2000) Discordance of p53 mutations of synchronous colorectal carcinomas. Mod Pathol 13:131–139

    CAS  PubMed  Google Scholar 

  25. 25.

    Tang R, Wang PF, Wang HC, Wang JY, Hsieh LL (2001) Mutations of p53 gene in human colorectal cancer: distinct frameshifts among populations. Int J Cancer 91:863–868

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Davidoff AM, Iglehart JD, Marks JR (1992) Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers. Proc Natl Acad Sci U S A 89:3439–3442

    CAS  PubMed  Google Scholar 

  27. 27.

    Burg SH van der, de Cock K, Menon AG, Franken KL, Palmen M, Redeker A et al (2001) Long lasting p53-specific T cell memory responses in the absence of anti-p53 antibodies in patients with resected primary colorectal cancer. Eur J Immunol 31:146–155

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs. Kornelia Polyak and Roger Greenberg (Harvard Medical School) for helpful suggestions during the preparation of the manuscript and Blaženka Ladika (University Hospital Sestre milosrdnice) for excellent assistance with the p53-Ab in vitro studies. This work was supported by the grant 134002 from the Croatian Ministry of Science and Technology (to J.L.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mirna Lechpammer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lechpammer, M., Lukač, J., Lechpammer, S. et al. Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy. Int J Colorectal Dis 19, 114–120 (2004). https://doi.org/10.1007/s00384-003-0553-5

Download citation

Keywords

  • Colorectal cancer
  • Tumor suppressor gene p53
  • Serum p53 antibodies
  • Cancer treatment
  • Follow-up