The pattern of expression of the receptor tyrosine kinases (RTK) EphB1, EphB2 and EphB4 in colorectal cancer

Abstract

Colorectal cancer (CRC) is a global health problem. It is the second leading cause of cancer related death worldwide and in Australia. Around 25% of CRC will experience recurrences postoperatively in the absence of lymph node metastasis and liver metastasis. We need to develop better diagnostic tools and more effective therapeutics. This will come through a thorough understanding of the molecular events in CRC progression.

Erythropoietin producing hepatoma (Eph) receptors are the largest family of the receptor tyrosine kinases (RTK). They are divided into two subfamilies, A and B, Together with their cognate ligands, they play integral role in different body organs during embryo development and in adulthood. EphB receptors are considered as key coordinator of proliferation and migration of the intestinal stem cells (ISCs). They are Wnt signalling target genes. They are distributed in a complimentary pattern with their ligands, ephrinB1 and ephrinB2, along the intestinal crypt axis.

Adenomatous polyposis coli gene mutation is considered as the initiating step in CRC development. It leads to Wnt signalling mutation and adenoma-carcinoma progression. Despite activation of Wnt signalling pathway, EphB receptors are inactivated during adenoma-carcinoma progression EphB1 and EphB2 receptors function as tumour suppressors in CRC, whereas for the EphB4 some studies found that EphB4 receptor is underexpressed whilst others found it overexpressed with the progression of the disease. It has also been suggested EphB4 expression is up-regulated as EphB2 expression is extinguished.

Using immunohistochemistry we investigated pattern of expression of the three receptors together, EphB1, EphB2 and EphB4, across three stages of CRC, SII, SIII, SIV, in lymph node metastasis, and in liver metastasis, in a total population of 148 CRC patients. We found that:

The three receptors are co-ordinately under-expressed in the primary CRC.

The receptors are further under-expressed in the liver metastasis.

The EphB1 receptor is under-expressed in most undifferentiated CRC and in liver metastasis.

The EphB4 receptors follow the same down-regulation pattern as the other two in both primary tumours and metastases.

There is no evidence that EphB2 –negative tumours express EphB4.

The importance of this study of EphB receptors expression pattern in CRC and in liver metastasis is that it gives a general picture about the status of the three receptors together across different stages of CRC, in lymph node metastasis, and in liver metastasis of the same patients. Understanding the pattern of expression of three receptors together in CRC, highlights the significance of these receptors in CRC, and in long term revolutionizes current anticancer drug treatment of the disease.