Research Papers:

Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib

Maria Serova, Annemilaï Tijeras-Raballand, Celia Dos Santos, Matthieu Martinet, Cindy Neuzillet, Alfred Lopez, Dianne C. Mitchell, Brad A. Bryan, Guillaume Gapihan, Anne Janin, Guilhem Bousquet, Maria Eugenia Riveiro, Ivan Bieche, Sandrine Faivre, Eric Raymond _ and Armand de Gramont

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Oncotarget. 2016; 7:38467-38486. https://doi.org/10.18632/oncotarget.9542

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Maria Serova1,2,3, Annemilaï Tijeras-Raballand1,2,3, Celia Dos Santos1,2,3, Matthieu Martinet1, Cindy Neuzillet2,3, Alfred Lopez4, Dianne C. Mitchell4, Brad A. Bryan4, Guillaume Gapihan3,5, Anne Janin3,5, Guilhem Bousquet5,6, Maria Eugenia Riveiro2,3, Ivan Bieche7, Sandrine Faivre2,3, Eric Raymond2,3,*, Armand de Gramont1,3,5,*

1AAREC Filia Research, Boulogne-Billancourt, France

2Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France

3INSERM, Paris, France

4Department of Biomedical Sciences, Center of Emphasis in Cancer Research at The Paul Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA

5Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris, France

6Department of Medical Oncology, Avicenne University Hospital (APHP- PRES Paris 13 University), Bobigny, France

7Laboratory of Oncogenetics, Institut Curie, Hôpital René Huguenin, St-Cloud, France

*These authors contributed equally to this work

Correspondence to:

Eric Raymond, email: [email protected]

Keywords: everolimus, sunitinib, renal cell carcinoma, angiogenesis, differentiation

Received: February 22, 2016     Accepted: May 04, 2016     Published: May 21, 2016


Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo. Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm.

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