Oncologic Trogocytosis of an Original Stromal Cells Induces Chemoresistance of Ovarian Tumours Arash Rafii1,2,5, Pejman Mirshahi1, Mary Poupot4, Anne-Marie Faussat1, Anne Simon 1 , Elodie Ducros1, Eliane Mery2, Bettina Couderc3, Raphael Lis3, Jerome Capdet3, Julie Bergalet3, Denis Querleu2, Francoise Dagonnet1, Jean-Jacques Fournie´ 4, Jean-Pierre Marie1, Eric Pujade-Lauraine1, Gilles Favre3, Jeanine Soria1, Massoud Mirshahi1* 1 UMRS 872 INSERM, Universite´ Pierre et Marie Curie-Paris 6 and Universite´ Paris Descartes, Equipe 18, Centre de Recherche des Cordeliers, Paris, France, 2 LFR 44, IFR 31, Institut Claudius Regaud, Toulouse, France, 3 INSERM U563, Department Innovations the´rapeutiques et Oncologie mole´culaire, Institut Claudius Regaud & Faculte´ des Sciences Pharmaceutiques, Toulouse, France, 4 INSERM U563, Centre de Physiopathologie de Toulouse Purpan, CHU Purpan, BP3028, Toulouse, France, 5 Department of Genetic Medicine and Obstetrics and Gynecology, WCMC-Qatar, Qatar Foundation, Doha, Qatar Abstract Background: The microenvironment plays a major role in the onset and progression of metastasis. Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneal cavity where interactions within the microenvironment might lead to chemoresistance. Mesothelial cells are important actors of the peritoneal homeostasis; we determined their role in the acquisition of chemoresistance of ovarian tumours. Methodology/Principal Findings: We isolated an original type of stromal cells, referred to as ‘‘Hospicells’’ from ascitis of patients with ovarian carcinosis using limiting dilution. We studied their ability to confer chemoresistance through heterocellular interactions. These stromal cells displayed a new phenotype with positive immunostaining for CD9, CD10, CD29, CD146, CD166 and Multi drug resistance protein. They preferentially interacted with epithelial ovarian cancer cells. This interaction induced chemoresistance to platin and taxans with the implication of multi-drug resistance proteins. This contact enabled EOC cells to capture patches of the Hospicells membrane through oncologic trogocytosis, therefore acquiring their functional P-gp proteins and thus developing chemoresistance. Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance. Conclusions/Significance: This is the first report of trogocytosis occurring between a cancer cell and an original type of stromal cell. This interaction induced autonomous acquisition of chemoresistance. The presence of stromal cells within patient’s tumour might be predictive of chemoresistance. The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy. Citation: Rafii A, Mirshahi P, Poupot M, Faussat A-M, Simon A, et al. (2008) Oncologic Trogocytosis of an Original Stromal Cells Induces Chemoresistance of Ovarian Tumours. PLoS ONE 3(12): e3894. doi:10.1371/journal.pone.0003894 Editor: Nils Cordes, Dresden University of Technology, Germany Received May 5, 2008; Accepted November 4, 2008; Published December 16, 2008 Copyright: 2008 Rafii Tabrizi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: hospicells@gmail.com Introduction Epithelial Ovarian carcinoma (EOC) is the sixth most common malignancy in woman and the leading cause of death from gynaecological cancer in the world [1]. EOC has a predisposition to metastatic involvement of the peritoneal cavity [2,3]. Late stage EOC is characterized by widespread peritoneal dissemination, ascites and a high rate of mortality with an overall survival ranging from 20 to 30% at 5 years after surgery depending the studies [4]. Platinum associated to taxans chemotherapy, is a standard treatment for ovarian cancer, and has achieved a high response rate. The development of drug-resistant cancer cells exhibiting the multidrug resistance phenotype is one of the major limitation of efficacy that has been illustrated in the literature for platinum or taxane chemotherapy [4,5]. A growing amount of studies are underlying the role of the microenvironnement in EOC development. Indeed the peritoneal sheath is composed by the mesothelium, a simple squamoid epithelium lining also the pleural and pericardial cavities [6]. The mesothelial cells play a major role in important physiologic functions such as dialysis, localization of infections and formation of abdominal adherences [7,8]. Their role in the dissemination of gastric, pancreatic and ovarian carcinoma has also been reported [9]. Several authors have demonstrated that ovarian cancer cells were able to attach to peritoneal mesothelial cells through activation of CD44 or beta-1 integrin [10–12]. Furthermore Burleson et al. have demonstrated that ovarian carcinoma ascitis spheroids (e.g. multi-cellular aggregates of ovarian cancer cells) were able to adhere to live but non-fixed human mesothelial cells [13,14]. Recently analysis of surgical specimens suggested that mesothelial cells may nurture peritoneal metastases through the production of growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). This confirmed the findings of Wilson who demonstrated that PLoS ONE | www.plosone.org 1 December 2008 | Volume 3 | Issue 12 | e3894