Molecular Medicine

, Volume 14, Issue 1–2, pp 45–54 | Cite as

Clinical Significance of Telomerase Activity in Peritoneal Disseminated Cells: Gastrointestinal Cancers

  • Inna L. Botchkina
  • David E. Rivadeneira
  • Kevin Watkins
  • Martin S. Karpeh
  • Galina I. Botchkina
Research Article


Early detection and accurate staging of gastrointestinal (GI) cancers are difficult. The aim of this study was to evaluate whether telomerase activity (TA) in exfoliated/disseminated epithelial cells could be used as a reliable marker for GI cancers. TA was evaluated with the real-time RTQ-TRAP in immunomagnetically sorted peritoneal epithelial cells from 60 patients undergoing surgical treatment. Thirty-two patients were clinically diagnosed with a variety of GI cancers: 1 had premalignant disease, 2 had history of GI cancers, and 25 patients were clinically negative for cancer. Here we report that all types and all cases of gastrointestinal cancers were telomerase positive, thereby demonstrating 100% sensitivity for cancer. Eighteen of 25 nonmalignant cases had undetectable levels of TA, 2 had low, and 5 of 25 expressed high TA levels. Because normal epithelial cells usually have low TA and a lesser tendency to exfoliate compared with cancer cells, it is of great importance to have close follow-up for these patients to exclude possible malignant disease. We conclude that RTQ-TRAP assessment of TA in immunomagnetically sorted peritoneal epithelial cells has 100% sensitivity and 100% negative predictive value for GI cancers, and therefore, can be considered as a valuable tool and useful addition to current standard diagnostic methods. Clinical significance of unusually high telomerase activity in some clinically negative for cancer cases requires further study.



We thank SBU Sensor CAT for support. We thank Barbara Smith, NP (SBU Medical Center) for irreplaceable help during the performance of this project. We also thank Dr. Henry Thode for his assistance with statistical analysis.


  1. 1.
    Pantel K, Woelfle U. (2006) Circulating tumor cells as an indicator of invasion. AACR Educ. Book 1:116–119.Google Scholar
  2. 2.
    Pantel K, von Knebel Doeberitz M. (2000) Detection and clinical relevance of micrometastatic cancer cells. Curr. Opin. Oncol. 12:95–101.CrossRefPubMedGoogle Scholar
  3. 3.
    Ludeman L, Shepherd NA. (2005). Serosal involvement in gastrointestinal cancer: its assessment and significance. Histopathiology 47:123–131.CrossRefGoogle Scholar
  4. 4.
    Noguchi Y et al. (2000) Is gastric carcinoma different between Japan and the United States? A comparison of patient survival among three institutions. Cancer 89:2237–2246.CrossRefPubMedGoogle Scholar
  5. 5.
    Kienle P, Koch M. (2002) Are “micrometastases” of the peritoneum equivalent to distant metastases? Dig. Surg. 19:453–458.CrossRefPubMedGoogle Scholar
  6. 6.
    Koppe MJ, Boerman OC, Oyen WJ, Bleichrodt RP. (2006) Peritoneal carcinomatosis of colorectal origin: Incidence and current treatment strategies. Ann. Surg. 243: 212–222.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Yoneda T, Hiraga T. (2005) Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem. Biophys. Res. Commun. 328:679–687.CrossRefPubMedGoogle Scholar
  8. 8.
    Burke EC, Karpeh MS Jr, Conlon KS, Brennan MF. (1998) Peritoneal lavage cytology in gastric cancer: an independent predictor of outcome. Ann. Surg. Oncol. 5:411–415.CrossRefPubMedGoogle Scholar
  9. 9.
    Bando E et al. (1999) Intraoperative lavage for cytological examination in 1297 patients with gastric carcinoma. Am. J. Surg.178:256–262.CrossRefPubMedGoogle Scholar
  10. 10.
    Jimenez RE, Warshaw AL, Fernandez-del Castillo C. (2000) Laparoscopy and peritoneal cytology in the staging of pancreatic cancer. J. Hepatobilliary Pancreat. Surg. 7:15–20.CrossRefGoogle Scholar
  11. 11.
    Yamamoto S, Akasu T, Fujita S, Moriya Y. (2003) Long-term prognostic value of conventional peritoneal cytology after curative resection for colorectal carcinoma. Jap. J. Clin. Oncol. 33:33–37.CrossRefGoogle Scholar
  12. 12.
    Cristofanilli M et al. (2004). Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer. NEJM, 531:781–791.CrossRefGoogle Scholar
  13. 13.
    Nieveen van Dijkum EJ et al. (1998) Cytology of peritoneal lavage performed during staging laparoscopy for gastrointestinal malignancies: is it useful? Ann. Surg. 228:728–733.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bentrem D, Wilton A, Mazumdar M, Brennan M, Coit D. (2005) The value of peritoneal cytology as a preoperative predictor in patients with gastric carcinoma undergoing a curative resection. Ann. Surg. Oncol. 12:347–353.CrossRefPubMedGoogle Scholar
  15. 15.
    Kodera Y et al. (1999) Prognostic value of positive findings in patients with gastric carcinoma undergoing a potentially curative resection. J. Surg. Oncol. 72:60–65.CrossRefPubMedGoogle Scholar
  16. 16.
    Blackburn EH. (1990) Telomeres and their synthesis. Science 3:489–490.CrossRefGoogle Scholar
  17. 17.
    Dong CK, Masutomi K, Hahn WC. (2005) Telomerase: regulation, function and transformation. Crit. Rev. Oncol. Hematol. 54:85–93.CrossRefPubMedGoogle Scholar
  18. 18.
    Hiyama E, Hiyama K. (2002) Clinical utility of telomerase in cancer. Oncogene 21:643–649.CrossRefPubMedGoogle Scholar
  19. 19.
    Stewart SA et al. (2002). Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. PNAS 99:12606–12611.CrossRefPubMedGoogle Scholar
  20. 20.
    Boldrini L et al. (2002). Evaluation of telomerase in the development and progression of colon cancer. Int. J. Mol. Med. 10:589–592.PubMedGoogle Scholar
  21. 21.
    Domont J et al. (2005). Catalytic subunit of human telomerase reverse transcriptase is an independent predictor of survival in patients undergoing curative resection of hepatic colorectal metastases: a multicenter analysis. Clin. Oncol. 23:3086–3093.CrossRefGoogle Scholar
  22. 22.
    Sanz-Casla MT et al. (2005). Telomerase activity as a prognostic factor in colorectal cancer. Onkologi 28:553–557.Google Scholar
  23. 23.
    Myung S et al. (2005) Clinical usefulness of telomerase for the detection of colon cancer in ulcerative colitis patients. J. Gastroenterol. Hepatol. 20:1578–1583.CrossRefPubMedGoogle Scholar
  24. 24.
    Wong S, Yu H, and So JB. (2006) Detection of telomerase activity in gastric lavage fluid: a novel method to detect gastric cancer. J. Surg. Res. 131:252–255.CrossRefPubMedGoogle Scholar
  25. 25.
    Kubota M, Yamana H, Sueyoshi S, Fujita H, Shirouzu K. (2002) The significance of telomerase activity in cancer lesions and the noncancerous epitheliumof the esophagus. Int. J. Clin. Oncol. 7:32–37.PubMedGoogle Scholar
  26. 26.
    Tominaga T et al. (2002) Telomerase activity and expression of human telomerase catalytic subunit gene in esophageal cancer. J. Gastroenterol. 37:488–490.CrossRefGoogle Scholar
  27. 27.
    Kyo S, Inoue M. (2002) Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy? Oncogene 21:688–697.CrossRefPubMedGoogle Scholar
  28. 28.
    Rohde V et al. (2000) Expression of the human telomerase reverse transcriptase is not related to telomerase activity in normal and malignant renal tissue. Clin. Cancer Res. 6:4803–4809.PubMedGoogle Scholar
  29. 29.
    Ohuchida K et al. (2005) Quantitative assessment of telomerase activity and hTERT mRNA levels in pancreatic juice samples for the diagnosis of pancreatic cancer. Clin Cancer Res 11:2285–2292.CrossRefPubMedGoogle Scholar
  30. 30.
    Li C, Liang Y, Wu M, Cai W. (2002) Telomerase activity analysis of esophageal carcinoma using microdissection-TRAP assay. Chin. Med. J. 115:1405–1408.PubMedGoogle Scholar
  31. 31.
    Mizumoto K, Tanaka M. (2004) Detection of telomerase activity in patients with pancreatic cancer. Methods Mol. Med. 103:199–206.Google Scholar
  32. 32.
    Botchkina GI et al. (2005) Noninvasive detection of prostate cancer by quantitative analysis of telomerase activity. Clin. Cancer Res. 11:3243–3249.CrossRefPubMedGoogle Scholar
  33. 33.
    Tomiki Y et al. (2000) Cancer cell exfoliation by preoperative colonoscopic examination. Digest. Endosc. 12:327–330.CrossRefGoogle Scholar
  34. 34.
    Koch M et al. (2004) Hematogenous tumor cell dissemination during colonoscopy for colorectal cancer. Surg. Endoscopy 18:587–591.CrossRefGoogle Scholar
  35. 35.
    Jaskolka JD et al. (2005) Needle tract seeding after radiofrequency ablation of hepatic tumors. J. Vasc. Interv. Radiol. 16:485–491.CrossRefPubMedGoogle Scholar
  36. 36.
    Alkhamesi NA, Ziprin P, Pfistermuller K, Peck DH, Darzi AW. (2005) ICAM-1 mediated peritoneal carcinomatosis, a target for therapeutic intervention. Clin. Exp. Metast. 22:449–459.CrossRefGoogle Scholar
  37. 37.
    Schmidt-Kittler O et al. (2003) From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proc. Natl. Acad. Sci. U.S.A., 100:7737–7742.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Weihrauch MR et al. (2002) Immunomagnetic enrichment and detection of micrometastases in colorectal cancer: correlation with established clinical parameters. J. Clin. Oncol. 20:4338–4343.CrossRefPubMedGoogle Scholar
  39. 39.
    Waguri N et al. (2003) Sensitive and specific detection of circulating cancer cells in patients with hepatocellular carcinoma; detection of human telomerase reverse transcriptase messenger RNA after immunomagnetic separation. Clin. Cancer Res. 9:3004–3011.PubMedGoogle Scholar
  40. 40.
    Hess JL, Atha DH, Xu JF, Highsmith WE Jr. (2004) Telomerase activity measurement in magnetically captured epithelial cells: comparison of slab-gel and capillary electrophoresis. Electrophoresis 25:1852–1859.CrossRefPubMedGoogle Scholar
  41. 41.
    Tokuda K et al. (2003) Clinical significance of CEA-mRNA expression in peritoneal lavage fluid from patients with gastric cancer. Int. J. Mol. Med. 11:79–84.PubMedGoogle Scholar
  42. 42.
    Tatsumoto N et al. (2000) High telomerase activity is an independent prognostic indicator of poor outcome in colorectal cancer. Clin. Cancer Res. 6:2696–2701.PubMedGoogle Scholar
  43. 43.
    Zendehrokh N, Dejmek A. (2005) Telomere repeat amplification protocol (TRAP) in situ reveals telomerase activity in three cell types: malignant cells, proliferartive mesothelial cells and lymphocytes. Modern Pathol. 18:189–196.CrossRefGoogle Scholar
  44. 44.
    Soreide K, Soreide JA. (2007) Bile duct cyst as precursor to biliary tract cancer. Ann. Surg. Oncol. 14:1200–1211.CrossRefPubMedGoogle Scholar
  45. 45.
    Mori K et al. (2007) Detection of minimal gastric cancer cells in peritoneal washings by focused microarray analysis with multiple mrkers: clinical implications. Ann. Surg. Oncol. 14:1694–1702.CrossRefPubMedGoogle Scholar
  46. 46.
    Musaers S. (2002) Mesothelial cells: Their structure, function and role in serosal repair. Respirology 7(3):171–191.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Inna L. Botchkina
    • 1
  • David E. Rivadeneira
    • 2
  • Kevin Watkins
    • 2
  • Martin S. Karpeh
    • 2
  • Galina I. Botchkina
    • 2
  1. 1.Department of PhysiologyUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Department of Surgery/Surgical OncologyStony Brook University Medical CenterStony BrookUSA

Personalised recommendations