EPH receptors are the largest family of receptor tyrosine kinases (RTKs), proteins that play a crucial role in many biological processes such as embryonic development, cell proliferation and differentiation. The first member of the EPH family was identified and cloned in 1987 by Hirai et al. from an Erytropoietin Producing Hepatocellular carcinoma cell line (EPH). To date, 16 receptors (14 found in mammals) and 9 ligands (8 in mammals) have been described. EPH receptors and ephrins (ligands) are implicated in a great variety of processes such as regulation of cell proliferation, migration, cell attachment and shape, axon guidance and synaptic plasticity. EPH receptors play important roles in tumorigenesis and metastasis and high levels of EPH have been related to angiogenesis in many tumor types including breast and lung.
Although overexpression of EPHB2 is observed in some tumor types, in gastrointestinal cancers, low levels of EPHB2 expression have been reported and found to be significantly associated with advance disease stage and poor survival (Lugli et al., 2005). In colorectal carcinoma (CRC), a progressive reduction in EPHB2 levels has been reported in the progression from normal epithelial cells to benign adenomas and to low and high stage tumors as well as lymph node and liver metastases, demonstrating a clear tendency to decreasing EPHB2 levels as CRC progress towards a more aggressive and metastatic phenotype. The loss of EPHB2 expression was also significantly associated with poor tumor differentiation and shorter patient survival. We have made some contributions towards increasing our understanding of the mechanisms responsible of this EPHB2 down-regulation in CRC (Alazzouzi et al 2005 Cancer Res 65:10170; Davalos et al 2007 Oncogene 26:308).
Similarly, EPHB4 expression in cancer is up- or down-regulated depending on the tumor type. A drastic increase of EPHB4 protein has been observed in endometrial hyperplasias and carcinomas, suggesting EPHB4 as an early indicator of malignant development. Moreover, EPHB4 overexpression has been associated with high histological grade and certain clinical stages in endometrial cancer. An increase in breast carcinoma has been also reported and high levels of EPHB4 correlated with histological grade and stage. In addition, strategies to block EPHB4 expression, both using siRNA and antisense led to dose-dependent reduction in cell survival and increased apoptosis in breast. In the normal colonic mucosa, we revealed a gradient of EPHB4 expression from the lower crypt to the colonic flat mucosa, and a substantial variability of EPHB4 expression in colorectal tumors from complete lack of immunoreactivity to very high levels of expression (Davalos et al 2006 Cancer Res 66:8943). Furthermore, our group has shown that low EPHB4 tumor levels identify a subset of colorectal cancer patients with poor prognosis and high risk of recurrence, and demonstrated that promoter hypermethylation was a common mechanism associated to the loss of EPHB4 expression. Moreover, reintroduction of EPHB4 into EPHB4-deficient tumor cells significantly reduced their long-term clonogenic potential, which taken together contributed to establish EPHB4 as a new putative tumor suppressor gene, and a useful prognostic marker in colorectal cancer (Davalos et al 2006 Cancer Res 66:8943).
