Combined expression of the non-receptor protein tyrosine kinases FAK and Src in primary colorectal cancer is associated with tumor recurrence and metastasis formation

de Heer, P.; Koudijs, M.M.; van de Velde, C.J.H.; Aalbers, R.I.J.M.; Tollenaar, R.A.E.M.; Putter, H.; Morreau, J.; van de Water, B.; Kuppen, P.J.K.

doi:10.1016/j.ejso.2008.05.003

« Previous Next »European Journal of Surgical Oncology
Volume 34, Issue 11 , Pages 1253-1261, November 2008

Combined expression of the non-receptor protein tyrosine kinases FAK and Src in primary colorectal cancer is associated with tumor recurrence and metastasis formation

P. de Heer
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
M.M. Koudijs
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
C.J.H. van de Velde
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
R.I.J.M. Aalbers
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
R.A.E.M. Tollenaar
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
H. Putter
- Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
J. Morreau
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
B. van de Water
- Leiden/Amsterdam Center for Drug Research, Division of Toxicology, Leiden University, Leiden, The Netherlands
P.J.K. Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Corresponding author. Leiden University Medical Center, Department of Surgery, P.O. Box 9600, Albinusdreef 2, 2300 RC, Leiden, The Netherlands, Tel.: +31 71 526 2309; fax: +31 71 526 6750.

Accepted 7 May 2008.

Abstract

Purpose

The protein tyrosine kinase focal adhesion kinase (FAK) and Src in association with phosphorylation of the adapter protein paxillin are essential in tumor metastasis formation. Elevated levels of FAK, Src and paxillin may increase the metastatic potential of colorectal tumor cells. The aim of the current study was to examine the expression of FAK, Src, and paxillin using immunohistochemistry in the context of disease progression and to evaluate its clinical significance as a prognostic factor.

Experimental design

The relationship between FAK, Src and paxillin levels and colorectal cancer progression was evaluated by immunohistochemistry in 104 colorectal cancer specimens with clinical follow up. In addition, FAK, Src and paxillin expression levels were quantified in 68 colorectal tumors and corresponding liver metastases.

Results

FAK and paxillin expression individually did not significantly impact time to recurrence (p=0.09, and p=0.89 respectively). Src expression was associated with tumor recurrence p=0.03. However, tumors that expressed both high FAK and Src levels had a significant shorter time to recurrence (p=0.004, hazard ratio: 2.98, 95% CI 1.14–6.31). FAK, Src and paxillin showed equivalent levels in corresponding liver metastases compared to the primary tumors (p=0.67, p=0.28 and p=0.34 respectively).

Conclusions

These findings show that high levels of FAK and Src combined were predictive for recurrence of colorectal cancer. In addition, expression of FAK, Src and paxillin in colorectal cancer were maintained in corresponding distant metastases.

Keywords: Focal adhesion kinase (FAK), Src, Paxillin, Colorectal cancer, Prognosis

Abbreviations: FAK, focal adhesion kinase, IHC, immunohistochemistry, OS, overall survival, DFS, disease free survival, TTR, time to recurrence