Mesenchymal Stem Cells Shed Amphiregulin at the Surface of Lung Carcinoma Cells in a Juxtacrine Manner 1,2 Oriane Carnet * , 3 , Julie Lecomte * , 3 , Anne Masset * , Irina Primac * , Tania Durré * , Ludovic Maertens * , Benoit Detry * , Silvia Blacher * , Christine Gilles * , Christel Péqueux * , Jenny Paupert * , Jean-Michel Foidart * , Guy Jerusalem † , Didier Cataldo * and Agnès Noel * *Laboratory of Tumor and Developmental Biology, GIGA- Cancer, University of Liège, B-4000 Liège, Belgium; † Department of Medical Oncology, Centre Hospitalier Universitaire (CHU), Sart Tilman, B-4000 Liège, Belgium Abstract Solid tumors comprise cancer cells and different supportive stromal cells, including mesenchymal stem cells (MSCs), which have recently been shown to enhance tumor growth and metastasis. We provide new mechanistic insights into how bone marrow (BM)–derived MSCs co-injected with Lewis lung carcinoma cells promote tumor growth and metastasis in mice. The proinvasive effect of BM-MSCs exerted on tumor cells relies on an unprecedented juxtacrine action of BM-MSC, leading to the trans-shedding of amphiregulin (AREG) from the tumor cell membrane by tumor necrosis factor-α–converting enzyme carried by the BM-MSC plasma membrane. The released soluble AREG activates cancer cells and promotes their invasiveness. This novel concept is supported by the exploitation of different 2D and 3D culture systems and by pharmacological approaches using a tumor necrosis factor-α–converting enzyme inhibitor and AREG-blocking antibodies. Altogether, we here assign a new function to BM-MSC in tumor progression and establish an uncovered link between AREG and BM-MSC. Neoplasia (2015) 17, 552–563 Introduction Cancers have long been considered the consequence of DNA mutations, particularly in oncogenes and tumor-suppressive genes that affect cell proliferation and survival [1,2]. However, these cancer cell– and genome-centered models have overlooked the complex nature of the tumoral tissue. Indeed, cancer cells are embedded in a tumor stroma composed of extracellular matrix and stromal cells, such as endothelial and lymphatic cells, immune and inflammatory cells, and (myo)fibroblasts [3]. The complex cross talk between tumor and stromal cells influences tumor cell behavior and facilitates metastatic dissemination to distant organs [1,4–7]. Cancer cells themselves are also able to alter the adjacent tissue to establish a permissive and supportive environment for tumor progression [3]. Fibroblastic-like cells can be derived from the activation of resident cells or the recruitment of bone marrow (BM)–derived mesenchymal stem cells (MSCs) [7,8]. MSCs are now recognized as an important source of carcinoma-associated fibroblasts (CAFs) [4]. MSCs are multipotent progenitor cells characterized by their capacity for self-renewal and differentiation into chondrocytes, osteocytes, adipocytes, fibroblasts, and other cell types [5,9]. Growing evidence has shown the crucial contribution of MSCs to malignant progression. Depending on the system used, MSCs have been shown to favor tumor growth and cancer metastasis by promoting angiogenesis, increasing the invasive properties of tumor cells, or preventing tumor cell recognition by the immune system [6,10–12]. On the other hand, few studies have www.neoplasia.com Volume 17 Number 7 July 2015 pp. 552–563 552 Address all correspondence to: Dr. Agnes Noel, Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie, CHU (B23), Sart-Tilman, B-4 000 Liège, Belgium. E-mail: Agnes.Noel@ulg.ac.be 1 This work was supported by grants from the Fonds National de la Recherche Scientifique (Belgium), the Fondation contre le Cancer (Foundation of Public Interest, Belgium), the Fonds spéciaux de la Recherche (University of Liège), the Centre Anticancéreux près l'Université de Liège, the Fonds Léon Fredericq (University of Liège), the Interuniversity Attraction Poles Programme–Belgian Science Policy (Brussels, Belgium), the Plan National Cancer (Service Public Fédéral), and the Actions de Recherche Concertées (University of Liege, Belgium). O.C., J.L., A.M., T.D., L.M., and B.D. each received a Televie-Fonds National de la Recherche Scientifique grant. 2 Conflict of interest: The authors declare no conflict of interest. 3 Equally contributed. Received 23 March 2015; Revised 23 June 2015; Accepted 2 July 2015 © 2015 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). 1476-5586 http://dx.doi.org/10.1016/j.neo.2015.07.002