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.
Oncotarget. 2016 May 25 [Epub]
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, Armand de Gramont
AAREC Filia Research, 1 place Paul Verlaine, Boulogne-Billancourt, France., AAREC Filia Research, 1 place Paul Verlaine, Boulogne-Billancourt, France., AAREC Filia Research, 1 place Paul Verlaine, Boulogne-Billancourt, France., AAREC Filia Research, 1 place Paul Verlaine, Boulogne-Billancourt, France., Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 bd du Général Leclerc, Clichy, France and INSERM UMR., Department 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., Department 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., Department 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., Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot) and INSERM, Paris France., Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot) and INSERM, Paris France., Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot) and INSERM, Paris France., Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 bd du Général Leclerc, Clichy, France and INSERM UMR., Laboratory of Oncogenetics, Institut Curie, Hôpital René Huguenin, St-Cloud, France., Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 bd du Général Leclerc, Clichy, France and INSERM UMR., Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 bd du Général Leclerc, Clichy, France and INSERM UMR., AAREC Filia Research, 1 place Paul Verlaine, Boulogne-Billancourt, France.