title: Human bone marrow stromal cells lose immunosuppressive and anti-inflammatory properties upon oncogenic transformation.
abstract: Because of their immunomodulatory properties, human bone marrow stromal cells (hBMSCs) represent promising stem cells for treatment of immune disorders. hBMSCs expansion precedes their clinical use, so the possibility that hBMSCs undergo spontaneous transformation upon long-term culture should be addressed. Whether hBMSCs retain immunosuppressive and anti-inflammatory properties upon oncogenic transformation remains unknown. Using sequentially mutated hBMSCs and spontaneously transformed hBMSCs, we report that, upon oncogenic transformation, hBMSCs lose immunosuppressive and anti-inflammatory properties in vitro and in vivo. Transcriptome profiling and functional assays reveal immune effectors underlying the loss of immunomodulation in transformed hBMSCs. They display a proinflammatory transcriptomic signature, with deregulation of immune and inflammatory modulators and regulators of the prostaglandin synthesis. Transformed hBMSCs lose their capacity to secrete the immunosuppressive prostacyclins prostaglandin E2 (PGE2) and PGI2 but produce proinflammatory thromboxanes. Together, the immunoregulatory profile adopted by hBMSCs largely depends on intrinsic genetic-molecular determinants triggered by genomic instability/oncogenic transformation.
authors.affiliation: Hospital Universitario de Asturias-Instituto Universitario de Oncología del Principado de Asturias, Oviedo 33006, Spain.
authors.forename: Rene
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, ON K1A 0K9, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosu-Myles
authors.affiliation: Ikerbasque, Basque Foundation of Science, Bilbao 20014, Spain; Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, San Sebastian 20014, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Aráuzo-Bravo
authors.affiliation: Josep Carreras Leukemia Research Institute, Cell Therapy Program, Medicine School, University of Barcelona, Barcelona 08036, Spain.
authors.forename: Angélica
authors.initials: A
authors.lastname: Horrillo
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra/CSIC, Granada 18016, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Gonzalez-Rey
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra/CSIC, Granada 18016, Spain. Electronic address: mdelgado@ipb.csic.es.
authors.forename: Mario
authors.initials: M
authors.lastname: Delgado
authors.affiliation: Josep Carreras Leukemia Research Institute, Cell Therapy Program, Medicine School, University of Barcelona, Barcelona 08036, Spain; Instituciò Catala de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain. Electronic address: pmenendez@carrerasresearch.org.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menendez
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D013931:Thromboxanes / Q000378:metabolism; D059467:Transcriptome
chemical_list: D013931:Thromboxanes; D011464:Epoprostenol; D015232:Dinoprostone