Ep-CAM Signalling and Function

Insight into molecular mechanisms of malignant transformation is changing the way cancer is being treated. Conventional treatment strategies target the DNA of all dividing cells, resulting in a significantly increased risk of collateral toxicity. Targeted strategies have now been developed that specifically disrupt oncogenically active cell surface receptors and endogenous signaling molecules. The epithelial cell adhesion molecule (Ep-CAM) has emerged as an attractive therapeutic target for patients with breast cancer. Ep-CAM protein overexpression has been described by our group in several human malignancies and was associated with poor prognosis. This effect on tumor behaviour is probably due to increased signaling via the Ep-CAM receptor. In fact, interruption of this process has been shown to cause anti-tumor effects. The proof of this principle is provided by clinical trial results showing an anti-tumor activity of Ep-CAM specific antibodies. Further clinical trials are currently in progress at our institution testing the efficacy of Ep-CAM specific antibodies in patients with Ep-CAM expressing breast cancer. If targeting the Ep-CAM antigen has proven to have antitumor effects, little is known about the precise molecular effects responsible for the anti-tumor activity of these therapeutic agents. Improved molecular characterization and greater understanding of the effects of Ep-CAM expression and targeting strategies will enable a better prediction of the action and potential side effects of this treatment strategy. The elucidation of potential common pathways with those of other therapeutic agents could help in defining additive and even synergistic anti- tumor activity with conventional treatment modalities.

The protein named EpCAM has been found on the majority of human cancers. In the last years it has been shown, that cancer patients that have high amounts of this protein in tumour cells have a more aggressive disease, tend to form more metastases and finally have a higher probability to die from the disease. These observations have led to the development of new oncologic treatments that target this EpCAM protein. As such, a new specific treatment named Catumaxomab (Removab) has been recently approved by the European Union for the use in patients with EpCAM positive cancers. The FWF project "EpCAM signalling and function" dealed with the molecular mechanism responsible for the more aggressive behaviour of EpCAM positive cancer cells. The research experiments showed the effect of high amounts of EpCAM in breast cancer cell lines. For this purpose, breast cancer cell line models with artificial EpCAM amounts were generated. In these models, we could show that EpCAM was responsible for activation of other cancer related molecules, suggesting an important role for EpCAM in breast cancer patients. However, the effect of EpCAM was not the same for all examined models, and additional factors must be evaluated to better define the role of this protein in breast cancer and other malignancies. These findings will help to more precisely block the mechanisms by which this EpCAM activates cancer cells, so as to ameliorate the survival of these patients. Moreover, the elucidation of additional factors that contribute to augment the efficacy of these new treatments will help to define patients that might have a particular good response to these new treatments.