title: uPAR-controlled oncolytic adenoviruses eliminate cancer stem cells in human pancreatic tumors.
abstract: Pancreatic tumors contain cancer stem cells highly resistant to chemotherapy. The identification of therapies that can eliminate this population of cells might provide with more effective treatments. In the current work we evaluated the potential of oncolytic adenoviruses to act against pancreatic cancer stem cells (PCSC). PCSC from two patient-derived xenograft models were isolated from orthotopic pancreatic tumors treated with saline, or with the chemotherapeutic agent gemcitabine. An enrichment in the number of PCSC expressing the cell surface marker CD133 and a marked enhancement on tumorsphere formation was observed in gemcitabine treated tumors. No significant increase in the CD44, CD24, and epithelial-specific antigen (ESA) positive cells was observed. Neoplastic sphere-forming cells were susceptible to adenoviral infection and exposure to oncolytic adenoviruses resulted in elevated cytotoxicity with both Adwt and the tumor specific AduPARE1A adenovirus. In vivo, intravenous administration of a single dose of AduPARE1A in human-derived pancreatic xenografts led to a remarkable anti-tumor effect. In contrast to gemcitabine AduPARE1A treatment did not result in PCSC enrichment. No enrichment on tumorspheres neither on the CD133(+) population was detected. Therefore our data provide evidences of the relevance of uPAR-controlled oncolytic adenoviruses for the elimination of pancreatic cancer stem cells.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Luciano
authors.initials: L
authors.lastname: Sobrevals
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Mato-Berciano
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Urtasun
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Mazo
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. Electronic address: cfillat@clinic.ub.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
mesh_terms: D000071916:AC133 Antigen; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D051927:CD24 Antigen / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000821:virology; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D010455:Peptides / Q000378:metabolism; D011401:Promoter Regions, Genetic; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000071916:AC133 Antigen; D017500:Adenovirus E1A Proteins; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D051927:CD24 Antigen; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D018960:Hyaluronan Receptors; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D003841:Deoxycytidine; D000093542:Gemcitabine