title: IL-4 receptor blockade abrogates satellite cell: rhabdomyosarcoma fusion and prevents tumor establishment.
abstract: Tumor cells of the muscle-related cancer alveolar rhabdomyosarcoma (aRMS) have dysregulated terminal myogenic differentiation that is characterized by continuous proliferation, decreased capacity to express markers of terminal differentiation, and inability of tumor cells to fuse to one another in the manner seen for normal myoblasts. Whether aRMS tumor cells can fuse with normal myogenic progenitors such as skeletal muscle stem cells (satellite cells) or myoblasts is unknown, as is the biological effect of fusion events if the phenomenon occurs. To study this possibility, we isolated primary satellite cells harboring a lacZ Cre-LoxP reporter gene for coculture with murine aRMS primary tumor cells expressing Cre. Results of in vitro and in vivo experiments demonstrated tumor cell-muscle cell progenitor fusion events as well as accelerated rates of tumor establishment and progression when satellite cells and derived muscle progenitors were coinjected with tumor cells in an orthotopic allograft model. Interleukin 4 receptor (IL-4R) blocking antibody treatment reversed fusion events in vitro and blocked tumor initiation and progression in vivo. Taken together, this study supports a potential role of tumor cell-host cell fusion and the strong therapeutic potential of IL-4R blockade to prevent the establishment of RMS tumors at new anatomical sites.
authors.affiliation: Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Pediatric Cancer Biology Program, Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Guangheng
authors.initials: G
authors.lastname: Li
authors.forename: Ken
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Megan
authors.initials: M
authors.lastname: Radka
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002459:Cell Fusion; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors*; D018232:Rhabdomyosarcoma, Alveolar / Q000473:pathology*; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology
chemical_list: D019948:Receptors, Interleukin-4
keywords: Fusion; IL-4; Rhabdomyosarcoma; Satellite cells