AIMS
Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in Australia. Identifying molecular targets for therapeutic intervention is essential to improve treatment. High expression of EphB4 receptors have been observed in several cancers. Targeting these receptors decreases the metastatic and proliferative potential of cancer cells and inhibits tumour vascularization indicating potential therapeutic application. However in CRC studies of EphB4 have yielded contradictory results.
METHODS
Cloned cell lines expressing high and low levels of EphB4 were derived from the SW480 human CRC cell line stably transfected with EphB4 expressing constructs together with “empty vector” control lines. These were studied in vitro for any changes in proliferation, apoptotic response, invasive and migration ability. In vivo the development and progression of tumours in orthotopic and subcutaneous models of cancer was assessed.
RESULTS
In the in vitro assays the only significant effect of EphB4 expression was enhanced migratory abilities of cells. In vivo experiments showed when tumours expressing high EphB4 levels were compared to control or low EphB4 tumours they were relatively homogenous with lower amounts of host derived stroma and reduced levels of central necrosis. In addition blood vessels supplying the tumour mass were thicker and more extensively networked on the surface of the tumour.
CONCLUSION
Our results are consistent with the suggestion that a higher expression of EphB4 receptors increases the level of vascularization in tumours. Targeting this receptor in the treatment of CRC could positively influence the prognosis of patients by hindering the vascularization of tumours. However, in vivo, EphB4 expression could promote repulsive interaction with Ephrin ligand expressing host stromal cells leading to restricted cancer growth and metastasis in vivo in a similar manner to that seen with another Eph receptor, EphB2 an issue we are addressing in ongoing studies.