Neural crest derived progenitor cells contribute to tumor stroma and aggressiveness in stage 4/M neuroblastoma

// Pedro Linares-Clemente 1, * , Diana Aguilar-Morante 1, * , Ismael Rodriguez-Prieto 1 , Gema Ramirez 3 , Carmen de Torres 5 , Vicente Santamaria 1, 3 , Diego Pascual-Vaca 1, 2 , Ana Colmenero-Repiso 1 , Francisco M. Vega 1 , Jaume Mora 5 , Rosa Cabello 4 , Catalina Marquez 3 , Eloy Rivas 2 and Ricardo Pardal 1 1 Instituto de Biomedicina de Sevilla (IBiS), Departamento de Fisiologia Medica y Biofisica, Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, Sevilla, Spain 2 Departamento de Anatomia Patologica, Hospital Universitario Virgen del Rocio, Sevilla, Spain 3 Departamento de Oncologia Pediatrica, Hospital Universitario Virgen del Rocio, Sevilla, Spain 4 Departamento de Cirugia Pediatrica, Hospital Universitario Virgen del Rocio, Sevilla, Spain 5 Departamento de Oncologia, Hospital Sant Joan de Deu, Barcelona, Spain * These authors contributed equally to this work Correspondence to: Ricardo Pardal, email: rpardal@us.es Pedro Linares-Clemente, email: plinaresclemente@gmail.com Keywords: neuroblastoma, neural crest-derived progenitors, angiogenesis, tumor stroma, smooth muscle actin (SMA) Received: November 04, 2016      Accepted: September 04, 2017      Published: September 21, 2017 ABSTRACT Pediatric tumors arise upon oncogenic transformation of stem/progenitor cells during embryonic development. Given this scenario, the existence of non-tumorigenic stem cells included within the aberrant tumoral niche, with a potential role in tumor biology, is an intriguing and unstudied possibility. Here, we describe the presence and function of non-tumorigenic neural crest-derived progenitor cells in aggressive neuroblastoma (NB) tumors. These cells differentiate into neural crest typical mesectodermal derivatives, giving rise to tumor stroma and promoting proliferation and tumor aggressiveness. Furthermore, an analysis of gene expression profiles in stage 4/M NB revealed a neural crest stem cell (NCSC) gene signature that was associated to stromal phenotype and high probability of relapse. Thus, this NCSC gene expression signature could be used in prognosis to improve stratification of stage 4/M NB tumors. Our results might facilitate the design of new therapies by targeting NCSCs and their contribution to tumor stroma.