title: CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide.
abstract: OBJECTIVE
  Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer.
  
  
  METHODS
  We isolated CD133(+) cells from a spontaneous pancreatic ductal adenocarcinoma mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133(+) cells in immune competent mice. Effect of Minnelide, a drug currently under phase I clinical trial, was studied on the tumors derived from the CD133(+) cells.
  
  
  RESULTS
  Our study showed for the first time that CD133(+) population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of prosurvival and proinvasive proteins compared to the CD133(-) non-TIC population. Our study further showed that Minnelide was very efficient in downregulating both CD133(-) and CD133(+) population in the tumors, resulting in a 60% decrease in tumor volume compared with the untreated ones.
  
  
  CONCLUSIONS
  As Minnelide is currently under phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy.
authors.affiliation: Authors' Affiliations: Division of Basic and Translational Research, Department of Surgery; and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.forename: Alice
authors.initials: A
authors.lastname: Nomura
authors.forename: Veena
authors.initials: V
authors.lastname: Sangwan
authors.forename: Rohit
authors.initials: R
authors.lastname: Chugh
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.forename: Ashok
authors.initials: A
authors.lastname: Saluja
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes; D004852:Epoxy Compounds; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010755:Organophosphates / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D006023:Glycoproteins; D016328:NF-kappa B; D010755:Organophosphates; D010455:Peptides; D010616:Phenanthrenes; C000606024:Prom1 protein, mouse; C579022:14-O-phosphonooxymethyltriptolide disodium salt