Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib

被引:27
作者
Serova, Maria [1 ,2 ,3 ]
Tijeras-Raballand, Annemilai [1 ,2 ,3 ]
Dos Santos, Celia [1 ,2 ,3 ]
Martinet, Matthieu [1 ]
Neuzillet, Cindy [2 ,3 ]
Lopez, Alfred [4 ]
Mitchell, Dianne C. [4 ]
Bryan, Brad A. [4 ]
Gapihan, Guillaume [5 ,6 ]
Janin, Anne [5 ,6 ]
Bousquet, Guilhem [5 ,6 ,7 ]
Riveiro, Maria Eugenia [2 ,3 ]
Bieche, Ivan [8 ]
Faivre, Sandrine [2 ,3 ]
Raymond, Eric [2 ,3 ]
de Gramont, Armand [1 ,5 ,6 ]
机构
[1] AAREC Filia Res, 1 Pl Paul Verlaine, Boulogne, France
[2] PRES Paris 7 Diderot, Beaujon Univ Hosp, AP HP, Dept Med Oncol, Clichy, France
[3] INSERM UMR, Paris, France
[4] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Ctr Emphasis Canc Res,Paul Foster Sch Med, El Paso, TX USA
[5] PRES Paris 7 Diderot, St Louis Univ Hosp, AP HP, Dept Pathol, Paris, France
[6] INSERM, Paris, France
[7] Univ Paris 13, Avicenne Univ Hosp, AP HP, Dept Med Oncol,PRES, Bobigny, France
[8] Hop Rene Huguenin, Inst Curie, Lab Oncogenet, St Cloud, France
关键词
everolimus; sunitinib; renal cell carcinoma; angiogenesis; differentiation; ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; CELL CARCINOMA; MESENCHYMAL TRANSITION; 1ST-LINE SUNITINIB; ANTITUMOR-ACTIVITY; RAD001; EVEROLIMUS; CYCLIN D1; CANCER; HYPOXIA;
D O I
10.18632/oncotarget.9542
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:38467 / 38486
页数:20
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