PURPOSE: The L1 adhesion molecule (CD171) is overexpressed in human ovarian and endometrial carcinomas and is associated with bad prognosis. Although expressed as a transmembrane molecule, L1 is released from carcinoma cells in a soluble form. Soluble L1 is present in serum and ascites of ovarian carcinoma patients. We investigated the mode of L1 cleavage and the function of soluble L1. EXPERIMENTAL DESIGN: We used ovarian carcinoma cell lines and ascites from ovarian carcinoma patients to analyze soluble L1 and L1 cleavage by Western blot analysis and ELISA. RESULTS: We find that in ovarian carcinoma cells the constitutive cleavage of L1 proceeds in secretory vesicles. We show that apoptotic stimuli like C2-ceramide, staurosporine, UV irradiation, and hypoxic conditions enhance L1-vesicle release resulting in elevated levels of soluble L1. Constitutive cleavage of L1 is mediated by a disintegrin and metalloproteinase 10, but under apoptotic conditions multiple metalloproteinases are involved. L1 cleavage occurs in two types of vesicles with distinct density features: constitutively released vesicles with similarity to exosomes and apoptotic vesicles. Both types of L1-containing vesicles are present in the ascites fluids of ovarian carcinoma patients. Soluble L1 from ascites is a potent inducer of cell migration and can trigger extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: We suggest that tumor-derived vesicles may be an important source for soluble L1 that could regulate tumor cell function in an autocrine/paracrine fashion.
PURPOSE: The L1 adhesion molecule (CD171) is overexpressed in humanovarian and endometrial carcinomas and is associated with bad prognosis. Although expressed as a transmembrane molecule, L1 is released from carcinoma cells in a soluble form. Soluble L1 is present in serum and ascites of ovarian carcinomapatients. We investigated the mode of L1 cleavage and the function of soluble L1. EXPERIMENTAL DESIGN: We used ovarian carcinoma cell lines and ascites from ovarian carcinomapatients to analyze soluble L1 and L1 cleavage by Western blot analysis and ELISA. RESULTS: We find that in ovarian carcinoma cells the constitutive cleavage of L1 proceeds in secretory vesicles. We show that apoptotic stimuli like C2-ceramide, staurosporine, UV irradiation, and hypoxic conditions enhance L1-vesicle release resulting in elevated levels of soluble L1. Constitutive cleavage of L1 is mediated by a disintegrin and metalloproteinase 10, but under apoptotic conditions multiple metalloproteinases are involved. L1 cleavage occurs in two types of vesicles with distinct density features: constitutively released vesicles with similarity to exosomes and apoptotic vesicles. Both types of L1-containing vesicles are present in the ascites fluids of ovarian carcinomapatients. Soluble L1 from ascites is a potent inducer of cell migration and can trigger extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: We suggest that tumor-derived vesicles may be an important source for soluble L1 that could regulate tumor cell function in an autocrine/paracrine fashion.
Authors: Masayuki Shimoda; Simona Principe; Hartland W Jackson; Valbona Luga; Hui Fang; Sam D Molyneux; Yang W Shao; Alison Aiken; Paul D Waterhouse; Christina Karamboulas; Franz M Hess; Takashi Ohtsuka; Yasunori Okada; Laurie Ailles; Andreas Ludwig; Jeffrey L Wrana; Thomas Kislinger; Rama Khokha Journal: Nat Cell Biol Date: 2014-08-24 Impact factor: 28.824
Authors: John D Whittard; Takeshi Sakurai; Melanie R Cassella; Mihaela Gazdoiu; Dan P Felsenfeld Journal: Mol Biol Cell Date: 2006-04-05 Impact factor: 4.138
Authors: Muhua Yang; Shalini Adla; Murali K Temburni; Vivek P Patel; Errin L Lagow; Owen A Brady; Jing Tian; Magdy I Boulos; Deni S Galileo Journal: Cancer Cell Int Date: 2009-10-29 Impact factor: 5.722
Authors: Paul Gutwein; Anja Schramme; Mohamed Sadek Abdel-Bakky; Kai Doberstein; Ingeborg A Hauser; Andreas Ludwig; Peter Altevogt; Stefan Gauer; Anja Hillmann; Thomas Weide; Christine Jespersen; Wolfgang Eberhardt; Josef Pfeilschifter Journal: J Biomed Sci Date: 2010-01-13 Impact factor: 8.410