Mutations of p53 and K-ras correlate TF expression in human colorectal carcinomas: TF downregulation as a marker of poor prognosis

  • Benqiang Rao
  • Yuanhong Gao
  • Jun Huang
  • Xiaoyan Gao
  • Xinhui Fu
  • Meijin Huang
  • Jiayin Yao
  • Jingping Wang
  • Wanglin Li
  • Junxiao Zhang
  • Huanliang Liu
  • Lei Wang
  • Jianping Wang
Original Article

Abstract

Background

Tissue factor (TF) is emphasized as the promising target in the future targeted therapy strategy for colorectal cancer (CRC). Recent evidence showed that TF expression is under the control of K-ras and p53. However, a comprehensive evaluation of TF expression, K-ras status, and p53 mutation has not been systematically analyzed. The aims of this study were to identify the percentages of positive TF in CRC patients; analyze the associations of TF expression, K-ras status, and p53 mutation; and evaluate the prognostic value of TF in CRC patients.

Methods

Ninety-six CRC samples were tested for TF expression, p53 mutation, and K-ras status by semiquantitative immunohistochemistry, Western blotting analysis, direct sequencing, and real-time quantitative PCR. Associations were sought with TF expression and clinical outcomes.

Results

TF expression was related to clinical stages, tumor differentiation, and tumor size. The positive proportions of TF expression on tumor cells and tumor vascular endothelial cells were 70% and 53% respectively in CRC patients. The positive proportion of TF co-expression on both cancer cells and tumor vascular endothelial cells was 40%, compared to an 83% total TF positive proportion in CRC patients. TF expression on CRC appeared to be increased with K-ras and/or p53 mutation(s). Disease-free survival and overall survival were significantly reduced in CRC patients with high TF expression.

Conclusions

TF may participate in both K-ras and p53 mutations involved in colorectal carcinogenesis and could be considered as a prognostic indicator for patients CRC.

Keywords

Tissue factor p53 K-ras Colorectal cancer 

References

  1. 1.
    Buller HR, van Doormaal FF, van Sluis GL et al (2007) Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 5:246–254PubMedCrossRefGoogle Scholar
  2. 2.
    Rak J, Milsom C, Yu J (2008) Tissue factor in cancer. Curr Opin Hematol 15:522–528PubMedCrossRefGoogle Scholar
  3. 3.
    Chen J, Bierhaus A, Schiekofer S et al (2001) Tissue factor—a receptor involved in the control of cellular properties, including angiogenesis. Thromb Haemost 86:334–345PubMedGoogle Scholar
  4. 4.
    Rickles FR (2006) Mechanisms of cancer-induced thrombosis in cancer. Pathophysiol Haemost Thromb 35:103–110PubMedCrossRefGoogle Scholar
  5. 5.
    Falanga A (2005) Thrombophilia in cancer. Semin Thromb Hemost 31:104–110PubMedCrossRefGoogle Scholar
  6. 6.
    Giesen PL, Rauch U, Bohrmann B et al (1999) Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 96:2311–2315PubMedCrossRefGoogle Scholar
  7. 7.
    Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451:914–918PubMedCrossRefGoogle Scholar
  8. 8.
    Tesselaar ME, Romijn FP, van der Linden IK et al (2007) Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 5:520–527PubMedCrossRefGoogle Scholar
  9. 9.
    Khorana AA, Francis CW, Menzies KE et al (2008) Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 6:1983–1985PubMedCrossRefGoogle Scholar
  10. 10.
    Kakkar AK, DeRuvo N, Chinswangwatanakul V et al (1995) Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 346:1004–1005PubMedCrossRefGoogle Scholar
  11. 11.
    Seto Shin-ichi, Onodera H, Kaido T et al (2000) Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis. Cancer 8(2):295–301CrossRefGoogle Scholar
  12. 12.
    Shigemori C, Wade H, Matsumoto K et al (1998) Tissue factor expression and metastatic potential of CRC. Thromb Haemost 80(6):894–898PubMedGoogle Scholar
  13. 13.
    Statom CA, Chetwood AS, Cameron IC et al (2007) The angiogenic switch occurs at the adenoma stage I the adenoma–carcinoma sequence in CRC. Gut 12l(13):213–220Google Scholar
  14. 14.
    Nakasaki T, Wada H, Shigemori C et al (2002) Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in CRC. Am J Hematol 69(40):247–254PubMedCrossRefGoogle Scholar
  15. 15.
    Lykke J, Nielsen HJ (2004) Haemostatic alterations in CRC: perspectives for future treatment. J Surg Omcol 88(4):269–275CrossRefGoogle Scholar
  16. 16.
    Yu JL, May L, Lhotak V et al (2005) Oncogenic events regulate tissue factor expression in CRC cells: implications for tumor progression and angiogenesis. Blood 105(4):1734–1741PubMedCrossRefGoogle Scholar
  17. 17.
    Sierko E, Wojtukiewicz MZ et al (2010) Expression of tissue factor pathway inhibitor (TFPI) in human breast and colon cancer tissue. Thromb Haemost 103:198–204PubMedCrossRefGoogle Scholar
  18. 18.
    Hu Z, Garen A (2000) Intratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugated for cancer immunotherapy in mouse models of prostatic cancer. Proc Natl Acad Sci USA 97(16):9221–9225PubMedCrossRefGoogle Scholar
  19. 19.
    Francis JL, Amirkhosravi A (2002) Effect of antihemostatic agents on experimental tumor dissemination. Semin Thromb Hemost 28(1):29–38PubMedCrossRefGoogle Scholar
  20. 20.
    Nilsson F, Kosmehl H, Zardi L, Neri D (2001) Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesisi, mediates the infarction of solid tumors in mice. Cancer Res 61:711–716PubMedGoogle Scholar
  21. 21.
    Jass JR (2006) CRC: a multipathway disease. Crit Rev Oncogenesis 12:273–287PubMedGoogle Scholar
  22. 22.
    Anwar S, Frayling IM, Scott NA et al (2004) Systematic review of genetic influences on the prognosis of CRC. Br J Surg 91:1275–1291PubMedCrossRefGoogle Scholar
  23. 23.
    Sameer AS, Pandith AS, Syeed N et al (2009) Molecular gate keepers succumb to gene aberrations in CRC in Kashmiri population, revealing a high incidence area. Saudi J Gastroenterol 15:244–252PubMedCrossRefGoogle Scholar
  24. 24.
    Smith G, Bounds R, Wolf H et al (2010) Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours—implications for personalised cancer medicine. Br J Cancer 102(4):693–703PubMedCrossRefGoogle Scholar
  25. 25.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767PubMedCrossRefGoogle Scholar
  26. 26.
    Mir MM, Dar NA, Gochhait S et al (2005) p53 mutation profile of squamous cell carcinomas of the esophagus in Kashmir (India): a high-incidence area. Int J Cancer 116:62–68PubMedCrossRefGoogle Scholar
  27. 27.
    Al-Kuraya KS (2009) K-RAS and TP53 mutations in colorectal carcinoma. Saudi J Gastroenterol 15(4):217–219PubMedCrossRefGoogle Scholar
  28. 28.
    Cho YB, Chun HK, Yun HR et al (2009) Histological grade predicts survival time associated with recurrence after resection for CRC. Hepatogastroenterology 56(94–95):1335–1340PubMedGoogle Scholar
  29. 29.
    Desolneux G, Burtin P, Lermite E et al. (2011) Prognostic factors in node-negative CRC: a retrospective study from a prospective database. Int J Colorectal Dis (in press)Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Benqiang Rao
    • 1
    • 6
  • Yuanhong Gao
    • 2
  • Jun Huang
    • 1
  • Xiaoyan Gao
    • 3
  • Xinhui Fu
    • 6
  • Meijin Huang
    • 1
  • Jiayin Yao
    • 4
  • Jingping Wang
    • 5
  • Wanglin Li
    • 1
  • Junxiao Zhang
    • 6
  • Huanliang Liu
    • 6
  • Lei Wang
    • 1
    • 6
  • Jianping Wang
    • 1
    • 6
  1. 1.Colorectal Surgery Department, The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  2. 2.Department of Radiation Oncology, Cancer Center, State Key Laboratory of Oncology in Southern ChinaSun Yat-sen UniversityGuangzhouChina
  3. 3.Department of Pediatrics, The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  4. 4.Department of Gastroenterology, The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  5. 5.Department of Gastroenterology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  6. 6.Institute of GastroenterologySun Yat-sen UniversityGuangzhouChina

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