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Open Access Research article

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

Ivan Bieche12, Sophie Vacher1, David Vallerand34, Sophie Richon56, Rana Hatem1, Ludmilla De Plater3, Ahmed Dahmani3, Fariba Némati3, Eric Angevin7, Elisabetta Marangoni3, Sergio Roman-Roman3, Didier Decaudin38 and Virginie Dangles-Marie1039*

Author Affiliations

1 Laboratoire d’Oncogénétique, 35 rue Dailly, Institut Curie - Hôpital Rene Huguenin, St Cloud, France

2 INSERM UMR745, Sorbonne Paris Cité, 4 avenue de l’Observatoire, Paris, France

3 Département de Recherche Translationnelle, Laboratoire d’Investigation Préclinique, Paris, France

4 Roche SAS, 30, cours de l'Ile Seguin, 92650 Boulogne-Billancourt, Cedex, France

5 IFR71, Sorbonne Paris Cité, 4 avenue de l’Observatoire, Paris, France

6 CNRS, UMR 144, Centre de Recherche, Institut Curie, 26 rue d’Ulm, Paris, France

7 Institut de Cancérologie Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France

8 Département d’Oncologie Médicale, Institut Curie, 26 rue d’Ulm, Paris, France

9 Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l’Observatoire, Paris, France

10 Research Center, Institut Curie, 12 rue Lhomond, F-75005 Paris, France

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BMC Cancer 2014, 14:178  doi:10.1186/1471-2407-14-178

Published: 13 March 2014

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.

Keywords:
Tumor vasculature; Patient-derived xenografts; Species-specific PCR assays; Endothelial markers; VEGFA-VEGFR1/2 signalings