THE ADHESION MOLECULE L1: A NOVEL PLAYER IN OVARIAN CANCER VASCULATURE

Ovarian cancer represents an outstanding clinical challenge because of its high mortality rate, mainly due to tumor relapse and chemoresistance. The identification of novel targets and strategies for the treatment of OC is clearly an unmet need in clinical oncology. In this context, drugs that interfere with tumor neovascularization have shown promising results in recent clinical trials. However, the beneficial effect of anti-angiogenic therapies is often modest and transient: in OC patients, for example, it has been observed only a limited increase in progression-free survival. Thus, the definition of novel druggable targets within the tumor vasculature will have profound implications, particularly for those tumor types, such as OC, that respond poorly to conventional anti-cancer treatments. L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily that was initially characterized as an adhesion molecule playing a key role in the development of nervous system. However, several studies have demonstrated its involvement in several types of human cancer, including ovarian carcinoma. In this context, L1 expression is generally associated with poor diagnosis, an aggressive behavior and advanced tumor stage. Moreover, L1 induces a motile and invasive phenotype, supporting metastatic spread, and promotes chemoresistance. Our laboratory has obtained compelling evidence that L1 is aberrantly expressed in tumor vasculature and exerts an unexpected, pleiotropic function in endothelial cells. Based on these findings and on the pivotal role of angiogenesis in ovarian cancer, in this work I have investigate the functional role of L1 within the OC-associated vasculature. My results revealed that L1 is particularly abundant in OC vasculature as compared to normal vessels. Moreover,, vascular L1 was found to be a causal player in OC progression, possibly due to an endothelial cell-autonomous effect on OC vascularization, concomitant to a positive regulation of ovarian cancer stem cell function. This research, besides giving insights into novel pathways involved in pathological angiogenesis, provides the rationale for exploring the clinical relevance of L1 expression and function in OC vessels and in their crosstalk with tumor cells, possibly opening new avenues for the development of innovative targeted therapies for OC malignancy.