title: Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings.
abstract: BACKGROUND
  Tumor endothelial transdifferentiation and VEGFR1/2 expression by cancer cells have been reported in glioblastoma but remain poorly documented for many other cancer types.
  
  
  METHODS
  To characterize vasculature of patient-derived tumor xenografts (PDXs), largely used in preclinical anti-angiogenic assays, we designed here species-specific real-time quantitative RT-PCR assays. Human and mouse PECAM1/CD31, ENG/CD105, FLT1/VEGFR1, KDR/VEGFR2 and VEGFA transcripts were analyzed in a large series of 150 PDXs established from 8 different tumor types (53 colorectal, 14 ovarian, 39 breast and 15 renal cell cancers, 6 small cell and 5 non small cell lung carcinomas, 13 cutaneous melanomas and 5 glioblastomas) and in two bevacizumab-treated non small cell lung carcinomas xenografts.
  
  
  RESULTS
  As expected, mouse cell proportion in PDXs -evaluated by quantifying expression of the housekeeping gene TBP- correlated with all mouse endothelial markers and human VEGFA RNA levels. More interestingly, we observed human PECAM1/CD31 and ENG/CD105 expression in all tumor types, with higher rate in glioblastoma and renal cancer xenografts. Human VEGFR expression profile varied widely depending on tumor types with particularly high levels of human FLT1/VEGFR1 transcripts in colon cancers and non small cell lung carcinomas, and upper levels of human KDR/VEGFR2 transcripts in non small cell lung carcinomas. Bevacizumab treatment induced significant low expression of mouse Pecam1/Cd31, Eng/Cd105, Flt1/Vegfr1 and Kdr/Vefr2 while the human PECAM1/CD31 and VEGFA were upregulated.
  
  
  CONCLUSIONS
  Taken together, our results strongly suggest existence of human tumor endothelial cells in all tumor types tested and of both stromal and tumoral autocrine VEGFA-VEGFR1/2 signalings. These findings should be considered when evaluating molecular mechanisms of preclinical response and resistance to tumor anti-angiogenic strategies.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.forename: David
authors.initials: D
authors.lastname: Vallerand
authors.forename: Sophie
authors.initials: S
authors.lastname: Richon
authors.forename: Rana
authors.initials: R
authors.lastname: Hatem
authors.forename: Ludmilla
authors.initials: L
authors.lastname: De Plater
authors.forename: Ahmed
authors.initials: A
authors.lastname: Dahmani
authors.forename: Fariba
authors.initials: F
authors.lastname: Némati
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: Département de Recherche Translationnelle, Laboratoire d'Investigation Préclinique, Paris, France. virginie.dangles-marie@curie.fr.
authors.forename: Virginie
authors.initials: V
authors.lastname: Dangles-Marie
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor