Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings

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• 作者：Ivan Bieche (91) (92)
  Sophie Vacher (91)
  David Vallerand (93) (94)
  Sophie Richon (95) (96)
  Rana Hatem (91)
  Ludmilla De Plater (93)
  Ahmed Dahmani (93)
  Fariba N茅mati (93)
  Eric Angevin (97)
  Elisabetta Marangoni (93)
  Sergio Roman-Roman (93)
  Didier Decaudin (93) (98)
  Virginie Dangles-Marie (100) (93) (99)
  
  91. Laboratoire d鈥橭ncog茅n茅tique ; Institut Curie - H么pital Rene Huguenin ; 35 rue Dailly ; St Cloud ; France
  92. INSERM UMR745 ; Sorbonne Paris Cit茅 ; 4 avenue de l鈥橭bservatoire ; Paris ; France
  93. D茅partement de Recherche Translationnelle ; Laboratoire d鈥橧nvestigation Pr茅clinique ; Paris ; France
  94. Roche SAS ; 30 ; cours de l鈥橧le Seguin ; 92650 ; Boulogne-Billancourt ; Cedex ; France
  95. IFR71 ; Sorbonne Paris Cit茅 ; 4 avenue de l鈥橭bservatoire ; Paris ; France
  96. CNRS ; UMR 144 ; Centre de Recherche ; Institut Curie ; 26 rue d鈥橴lm ; Paris ; France
  97. Institut de Canc茅rologie Gustave Roussy ; 39 rue Camille Desmoulins ; Villejuif ; France
  98. D茅partement d鈥橭ncologie M茅dicale ; Institut Curie ; 26 rue d鈥橴lm ; Paris ; France
  100. Research Center ; Institut Curie ; 12 rue Lhomond ; F-75005 ; Paris ; France
  99. Sorbonne Paris Cit茅 ; Universit茅 Paris Descartes ; 4 avenue de l鈥橭bservatoire ; Paris ; France
  
• 关键词：Tumor vasculature ; Patient ; derived xenografts ; Species ; specific PCR assays ; Endothelial markers ; VEGFA ; VEGFR1/2 signalings
• 刊名：BMC Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：14
• 期：1
• 全文大小：555 KB
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  34. The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/14/178/prepub
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

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.