An angiogenic function for E-cadherin in ovarian cancer

Abstract

The loss of E-cadherin, a cell-cell adhesion molecule, is a well-established marker for metastasis of cancer. Although E-cadherin is synthesized as a transmembrane molecule, it can be cleaved of the ectodomain and released in a soluble form (sE-cad), and this accounts a key mechanism for a rapid reduction of functional E-cadherin at the cell surface. Yet, very little is known about how this important protein dictates the metastasis of these tumors. In ovarian cancer, a highly metastatic tumor that is rapidly lethal, sE-cad is highly expressed in the serum and metastatic ascites of ovarian carcinoma patients. Despite many studies focused on the role of E-cadherin loss in weakening cell-cell adhesion, whether sE-cad has biological activity in itself remain virtually unknown. Here we show for the first time that sE-cad can transduce angiogenic signals. sE-cad was also present in the culture supernatant of ovarian cancer lines. sE-cad of supernatant and a recombinant sE-cad-Fc chimera potently stimulated the migration of, permeability, and tubulogenesis by human umbilical vein endothelial cells in vitro. sE-cad also promoted functional neovascularization in a Matrigel implant model in vivo. These effects could be reversed by neutralizing anti-sE-cad, confirming that the effects were sE-cad specific. In addition, we found that sE-cad bound to VE-cadherin, an effect mediated through the phosphatidylinositol 3-kinase/Akt-β-catenin pathway. These results unravel a new and important piece to the complex biology of tumor angiogenesis and metastasis, and provide insights of novel mechanisms regulating angiogenesis. (This study was supported by RGC grant HKU781013). ©2014 American Association for Cancer Research.