Brachyury expression predicts poor prognosis at early stages of colorectal cancer

Abstract

Although survival rates of colon cancer patients diagnosed at an early stage (T1-2N0M0; Dukes A) vary considerably according to the studies cited, several studies indicate development of distant metastases already occurring in a considerable percentage of these patients leading to the death of the patients. This particular high risk group cannot be identified properly as no marker exists to identify these patients. As the Wnt/Win pathway plays a crucial role in metastasis formation in colorectal carcinoma, we analysed whether the transcription factor brachyury critically involved in this pathway may predict metastasis formation in these patients.

The expression of brachyury-homologous (T) was immunohistochemically analysed in 748 patients and the data were correlated with classical and newer prognostic markers in colorectal cancer.

Early stages colorectal cancer patients (T1-2N0M0, Dukes A) showed a significantly decreased survival when brachyury was expressed in the tumour tissue while no correlation was observed in later tumour stages. Hence a subset of colorectal cancers exists in which the ability to metastasise is already present at early stages of tumour growth and this high risk group can now be detected by immunohistochemistry.

Introduction

Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the Western world.¹ As in other cancers, cancer-related deaths in colorectal carcinoma can be attributed to the fact that colorectal cancer metastasises and once generalised metastases have been formed, mostly no cure is possible.

While it was initially proposed that colorectal carcinogenesis is a stepwise process in which metastasis is a relatively late mutational event,² later data showed that multiple alternative genetic pathways to colorectal cancer exist indicating that the linear model of Fearon and Vogelstein is too simplistic for the molecular events occurring during malignant progression in many colorectal cancer patients.³ The latter hypothesis implies that cancer patients should exist in which the ability to metastasise is already present at an early stage of tumour development. This point of view is underscored by clinical studies which show that a considerable number of early stage colorectal cancer patients develop metastases later on.⁴

We therefore searched for such a protein that might represent an early genetic marker for metastatic behaviour of colorectal cancer. In our search we concentrated on the Wnt/β-catenin pathway, as proteins of this pathway regulate the epithelial mesenchymal transition (EMT), a process thought to be vital for metastasis formation.⁵ EMT is tightly regulated by transcription factors and a particular transcription factor involved in this pathway, namely brachyury, has recently been implicated to play a pivotal role in tumour growth and metastasis.⁶ Brachyury, also known as T, is a member of the T-box family, whose expression is regulated by the Wnt signalling pathway which in turn is mediated by the β-catenin/TCF4 complex.⁷ This complex has been shown to be expressed in the proliferative compartment of the colonic mucosa, where the intestinal epithelial stem cells reside.

Although initially the expression of the brachyury protein had been identified as a definitive diagnostic marker of chordoma,⁸ recent studies showed that brachyury is also expressed in tumours of the small intestine, stomach, kidney, bladder, uterus, ovary and testis, as well as in cell lines derived from lung, colon and prostate carcinomas, however, not in the vast majority of normal tissues tested⁹ making it an interesting target as a prognostic marker in cancer.

Until now, the role of brachyury in malignant progression of colorectal cancer has not been investigated. The aim of this study was to evaluate whether brachyury is expressed in colorectal cancer at all, and if, whether it shows a correlation with different stages and grading and finally, whether it may be a suitable prognostic marker for colorectal cancer.