The role of endothelial cells in tumour angiogenesis translated to clinical relevance

Abstract

Conventional chemotherapy has shown its effectivity in the treatment of many cancers types. Nevertheless, because of the non-specificity of the agents, this tumor destroying capacity goes hand in hand with damage to the healthy tissues, expressed as unwanted toxicity. The past decades this treatment emerging toxicity seemed to be well managed by standard care strategies. Still, it is desirable to only target the tumor cells, resulting in a more effective therapeutical potential of anti cancer agents and less unwanted side effects. From that point of view, in the treatment of cancer the focus has shifted from general cytotoxic agents to a more cell specific, targeted therapy. A multitude of ‘targeting’ agents has been explored and some of them have already proven their therapeutical activity and are nowadays implemented as standard care for certain cancer types. In this dissertation I focussed on endothelial cells and their role and implications in the treatment of cancer. These cells reconstitute a specific target for therapy as they are the building blocks for the vasculature, and in specific tumor vasculature. Endothelial cells can be inhibited by interference in the vascular endothelial growth factor (VEGF) signalling pathway, a growth factor involved in endothelial cell proliferation, migration and function. VEGF inhibiting agents reconstitute a powerful target for therapy, as single agent therapy, but also as part of combinatorial regimens. Within this spectrum, as having an important function in normal physiology, endothelial cells also play an important role in VEGF inhibition induced toxicity. Contrary to expectations, despite the specificity of this kind of treatment, these endothelial cells play also an important role in normal physiology and this is reflected in a specific toxicity profile. Endothelial cell/ angiogenesis inhibition by blocking VEGF-mediated signaling can result in serious side effects in a substantial proportion of patients. Most of these side effects seem to be manageable, but likely will become more problematic when survival increases. Therefore it is desirable to elucidate the underlying pathophysiological mechanisms, to provide new insights into the pathogenesis of this toxicity in order to manage these side effects effectively. Finally this could result in the development of more specific angiogenesis inhibitors. Although being claimed as promising agents, major encumbrances still exist consisting of the considerable side effects especially when treatment is continued for a longer period, the apparently inevitable resistance to this kind of agents on the long run and the substantial costs of the treatment. For that reason, it is desirable to be able to select only those patients who will benefit from treatment and to recognize resistance. By means of a predictieve biomarker it might be possible to make this selection, and consequently to prevent overtreatment and unneeded toxicity and to early recognize resistance to the drug. The final implication of endothelial cells discussed in this thesis is that they would be candidates for the role as a surrogate biomarker in angiogenesis inhibition. Before this last application can be implemented, general agreement of the true identity and the most proper way to enumerate these cells should be achieved.