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  • Original Article
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Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

Oncogene volume 25, pages 3150–3159 (2006)Cite this article

Abstract

In vivo neuroblastoma (NB) xenograft model, resistant to the DNA-topoisomerase I inhibitor irinotecan (CPT-11), has been established to study resistance mechanisms acquired in a therapeutic setting. Common mechanisms of resistance were not involved in this resistance. Thus, we compared the gene expression profiles of sensitive, resistant, and reverted tumors using cDNA expression arrays. Expression of selected transcripts was confirmed by quantitative real-time PCR. We found that pleiotrophin (PTN), a heparin-binding growth factor, was the only gene significantly affected: PTN gene expression was downregulated in all resistant tumors (8–14-fold) as compared to sensitive tumors, and was increased (2–4-fold) in all reverted tumors as compared to resistant tumors. PTN thus appeared to be a likely candidate gene associated with resistance to CPT-11 in this in vivo model. To investigate the direct implication of PTN in NB, we transfected two NB cell lines with RNA interferences in order to silence PTN. PTN failed to demonstrate implication in resistance to CPT-11 in vitro but could influence sensitivity to CPT-11 exclusively through an in vivo mechanism. Indeed, vasculature was significantly enhanced in resistant NB xenografts compared to sensitive and reverted xenografts, and we suggest that PTN is acting in our resistant in vivo NB model as an angiostatic factor.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

NB:

neuroblastoma

PTN:

pleiotrophin

siRNA:

small interfering RNA

pRS:

pRetroSuper

MDR:

multidrug resistance

MRP:

multidrug resistance-associated protein

BCRP:

breast cancer resistance protein

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Acknowledgements

We thank Patrice Ardouin and the staff in the Animal Experimentation Unit, Institut Gustave-Roussy, for the care of the animals; Dr Marjorie Flahaut, Dr Roland Meier and Katya Auderset for excellent technical support from Department of Pediatric Oncology Research, CHUV, Lausanne, Switzerland; Elisabeth Connault from Institut Gustave-Roussy for excellent technical support and Lorna Saint-Ange from Institut Gustave-Roussy for editing the manuscript. We thank the Ligue National Contre le Cancer and the Association pour la Recherche sur le Cancer for supporting this work.

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Authors and Affiliations

  1. Pharmacology and New Treatments of Cancer: UPRES-EA, 3535 Institut Gustave Roussy, Villejuif, France

    L Calvet, B Geoerger, M Regairaz, L Machet, J Morizet & G Vassal

  2. Vectorology and gene transfer UMR 8121, Institut Gustave-Roussy, Villejuif, France

    P Opolon

  3. Pediatric Department CHUV, Pediatric Oncology Research, Lausanne, Switzerland

    J-M Joseph

  4. Laboratoire d'Imagerie du Petit Animal (LIPA), Institut Gustave Roussy, Villejuif, France

    N Elie

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  1. L Calvet
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Correspondence to G Vassal.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Calvet, L., Geoerger, B., Regairaz, M. et al. Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan. Oncogene 25, 3150–3159 (2006). https://doi.org/10.1038/sj.onc.1209348

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