Skip to main content
SpringerLink
Log in

Single alteration ofp53 or E-cadherin genes can alter the surgical resection benefit in an experimental model of colon cancer

  • Original Contributions
  • Published:
Diseases of the Colon & Rectum

Abstract

PURPOSE:p53 and E-cadherin mutations are associated with a high risk of metastatic potential and local recurrence after colorectal surgery. LoVo, a human colon cancer cell line expressing a wild-typep53 and a normal E-cadherin, was studied. Clone LoVo-XC17 was obtained from LoVo cells transfected with a vector bearing ap53 273his mutation. Clone LoVo-92R4 was obtained from LoVo by culture cells with an E-cadherin down-regulation. LoVo, LoVo-XC17, and LoVo-92R4 were studied forin vivo behavior in a surgical intracolonic graft model. METHODS: Ten nude mice were used per cell line. A colonic tumor was obtained by tumor implantation into the cecal wall. The cecal tumor was resected at Day 15; at this time the volumes of the different tumors were similar. RESULTS: Surgical resection of the LoVo tumor led to 100 percent disease-free animals at one month. Surgical resection of mice grafted with the LoVo-XC17 line did not cure any mice (0/10;P = 0.001). Mice had local recurrences (10/10), mesenteric lymph node metastases (9/10), liver metastases (2/10), and peritoneal carcinomatosis (8/10). Surgical resection of LoVo-92R4 tumors led to cures in 30 percent (3/10), whereas 70 percent had isolated mesenteric lymph node metastases (7/10;P = 0.003). CONCLUSION: In this model surgical tumor resection was consistently effective for colonic tumors with functionalp53 and E-cadherin, it was consistently ineffective with tumors displaying a mutatedp53, and it was partially effective with E-cadherin-deficient tumors. This study shows that the alteration of a single gene can be associated with a profound alteration of surgical resection benefit.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Silverberg E, Lubera J. Cancer statistics, 1988. Ca Cancer J Clin 1988;38:5–22.

    Google Scholar 

  2. Hamilton JM, Friedman MA. Adjuvant chemotherapy of colorectal cancer. In: Wanebo HJ, ed. Surgery for gastrointestinal cancer. A multidisciplinary approach. Philadelphia: Lippincott-Raven, 1977.

    Google Scholar 

  3. Carson DA, Lois A. Cancer progression and p53. Lancet 1995;346:1009–11.

    Google Scholar 

  4. Vogelstein B, Kinzler KW. p53 function and dysfunction. Cell 1992;70:523–6.

    Google Scholar 

  5. Levi E, Stryker SJ, Rao MS. p53 protein overexpression in colorectal tumors from patients with familial adenomatous polyposis: is it an early or a late event? Am J Gastroenterol 1996;91:11–4.

    Google Scholar 

  6. Carder PJ, Cripps KJ, Morris R,et al. Mutation of the p53 gene precedes aneuploid clonal divergence in colorectal carcinoma. Br J Cancer 1995;71:215–8.

    Google Scholar 

  7. Maruyama K, Tanaka T, Baba S, Nakamura S, Endo Y, Sugimura H. p53 accumulation in colorectal cancer with hepatic metastasis. Jpn J Cancer Res 1996;87:368–6.

    Google Scholar 

  8. Kastrinaksis WV, Ramchurren N, Rieger KM,et al. Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression. Oncogene 1995;11:647–52.

    Google Scholar 

  9. Hamelin R, Laurent-Puig P, Olschwang S,et al. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 1994;106:42–8.

    Google Scholar 

  10. Goh H-S, Yao J, Smith DR. P53 point mutation and survival in colorectal cancer patients. Cancer Res 1995;55:5217–21.

    Google Scholar 

  11. Kirsch DG, Kastan MB. Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 1998;16:3158–68.

    Google Scholar 

  12. Bracke ME, Van Roy FM, Mareel MM. The E-cadherin/catenin complex in invasion and metastasis. Curr Top Microbiol Immunol 1996;213:123–61.

    Google Scholar 

  13. Nabeshima K, Asada Y, Inoue T,et al. Modulation of E-cadherin expression in TPA-induced cell motility: well-differentiated human adenocarcinoma cells move as coherent sheets associated with phosphorylation of E-cadherin-catenin complex. Lab Invest 1997;76:139–51.

    Google Scholar 

  14. Debruyne P, Vermeulen S, Mareel M. The role of E-cadherin/catenin complex in gastrointestinal cancer. Acta Gastroenterol Belg 1999;62:393–402.

    Google Scholar 

  15. Dorudi S, Handby AM, Poulsom R, Northover J, Hart I. Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome. Br J Cancer 1995;71:614–6.

    Google Scholar 

  16. Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 1990;50:6130–8.

    Google Scholar 

  17. Tsukui H, Pocard M, Salmon RJ,et al. Orthotopic implantation of human colon cancer into nude mice. Methodology and physiological interest. Gastroenterol Clin Biol 1994;18:1112–8.

    Google Scholar 

  18. Pocard M, Tsukui H, Salmon RJ, Dutrillaux B, Poupon M-F. Efficiency of orthotopic xenograft models for human colon cancers. In Vivo 1996;10:463–70.

    Google Scholar 

  19. Kuo T-H, Kubota T, Watanabe M,et al. Early resection of primary orthotopically-growing human colon tumor in nude mouse prevents liver metastasis: further evidence for patient-like hematogenous metastatic route. Anticancer Res 1993;13:293–8.

    Google Scholar 

  20. Casares S, Ionov Y, Ge HY, Stanbridge E, Perucho M. The microsatellite mutator phenotype of colon cancer cells is often recessive. Oncogene 1995;11:2303–10.

    Google Scholar 

  21. Pocard M, Chevillard S, Villaudy J, Poupon MF, Dutrillaux B, Remvikos Y. Different p53 mutations produce distinct effects on the ability of colon carcinoma cells to become blocked at the G1/S boundary after irradiation. Oncogene 1996;12:875–82.

    Google Scholar 

  22. Vermeulen SJ, Bruyneel EA, Bracke ME,et al. Transition from the noninvasive to the invasive phenotype and loss of alpha-catenin in human colon cancer cells. Cancer Res 1995;55:4722–8.

    Google Scholar 

  23. Lefrançois D, Olschwang S, Delattre O,et al. Preservation of chromosome and DNA characteristics of human colorectal adenocarcinomas after passage in nude mice. Int J Cancer 1989;44:871–8.

    Google Scholar 

  24. Levine AJ, Perry ME, Chang A,et al. The 1993 Walter Hubert Lecture: the role of p53 tumour-suppressor gene in tumorigenesis. Br J Cancer 1994;69:409–16.

    Google Scholar 

  25. Vermeulen PB, Roland L, Mertens V,et al. Correlation of intratumoral microvessel density and p53 protein overexpression in human colorectal adenocarcinoma. Microvasc Res 1996;51:164–74.

    Google Scholar 

  26. Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:1582–4.

    Google Scholar 

  27. Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler KW, Vogelstein B. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 1992;256:827–30.

    Google Scholar 

  28. Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991;51:3075–9.

    Google Scholar 

  29. Karatzas G, Karayiannakis AJ, Syrigos KN,et al. E-cadherin expression correlates with tumor differentiation in colorectal cancer. Hepatogastroenterology 1999;46:232–5.

    Google Scholar 

  30. Hugh TJ, Dillon SA, Taylor BA, Pignatelli M, Poston GJ, Kinsella AR. Cadherin-catenin expression in primary colorectal cancer: a survival analysis. Br J Cancer 1999;80:1046–51.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. From Cytogénétique Moléculaire et Oncologie, Institut Curie, Paris, France

    Marc Pocard M.D., Ph.D., Rui Bras-Gonçalves Ph.D., Bernard Dutrillaux M.D., Ph.D. & Marie-France Poupon M.D., Ph.D.

  2. the Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium

    Philip Debruyne M.D. & Marc Mareel M.D., Ph.D.

Authors
  1. Marc Pocard M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Debruyne M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui Bras-Gonçalves Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc Mareel M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernard Dutrillaux M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marie-France Poupon M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by the Ligue Nationale contre le Cancer and by the Société Nationale Française de Gastroentérologie, with grants for Marc Pocard. Philip Debruyne is a research assistant with the “Bijzonder Onderzoeks Fonds Universiteit Gent,” supported in part by the Belgian Cancer association and the Fund for Scientific Research—Flanders.

Read at The American Society of Colon and Rectal Surgeons' 100th Anniversary and Tripartite Meeting, Washington, D.C., May 1 to 6, 1999.

About this article

Cite this article

Pocard, M., Debruyne, P., Bras-Gonçalves, R. et al. Single alteration ofp53 or E-cadherin genes can alter the surgical resection benefit in an experimental model of colon cancer. Dis Colon Rectum 44, 1106–1112 (2001). https://doi.org/10.1007/BF02234630

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02234630

Key words

Search

Navigation