Sialyl Lewis X is essential for early stage ovarian tumor metastasis through modulation of tumor-mesothelial adhesion

Abstract

Ovarian cancer has the highest mortality of all gynecologic tumors with a poor prognosis characterized by widespread peritoneal dissemination and malignant ascites. Successful adhesion to the peritoneal mesothelium represents a first and pivotal step for the onset of the metastatic cascade. This tumor cell lodgement is mediated by engagement of specialized adhesion molecules that function under ascetic shear condition. However, very little is known about this particular interaction. It is increasingly clear that only a minority of cancer stem/tumor‐initiating cells (CSCs) have the capability to initiate metastasis. Here we have identified the highly metastatic population of CSCs (HM‐CSCs). Importantly, in a three‐dimensional microfluidic platform, we revealed for the first time that sialyl Lewis X which is unique in HM‐CSCs may mediate ovarian tumor interaction with peritoneal mesothelial cells under shear stress of ascitic flow. HM‐CSCs exhibit slower rolling velocity and bind more firmly to the peritoneal mesothelium than NM‐CSCs. This interaction is mediated by P‐selectin expressed by the peritoneal mesothelium and sialyl Lewis x (sLex) expressed on HM‐CSCs. Using canonical biochemical assays, we found that enzymes involved in the synthesis of sLex are significantly increased in HM‐CSCs compared with NM‐CSCs, with a concomitant higher cell surface expression of sLex. These data define a critical role for sialyl Lewis X in ovarian cancer metastasis through modulation of tumor‐mesothelium communication, and that its targeting may represent a potential therapeutic advantage.