title: Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib.
abstract: 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.
authors: AAREC Filia Research, Boulogne-Billancourt, France.|Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Maria
authors: M
authors: Serova
authors: AAREC Filia Research, Boulogne-Billancourt, France.|Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Annemilaï
authors: A
authors: Tijeras-Raballand
authors: AAREC Filia Research, Boulogne-Billancourt, France.|Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Celia
authors: C
authors: Dos Santos
authors: AAREC Filia Research, Boulogne-Billancourt, France.
authors: Matthieu
authors: M
authors: Martinet
authors: Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Cindy
authors: C
authors: Neuzillet
authors: 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.
authors: Alfred
authors: A
authors: Lopez
authors: 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.
authors: Dianne C
authors: DC
authors: Mitchell
authors: 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.
authors: Brad A
authors: BA
authors: Bryan
authors: INSERM, Paris France.|Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris France.
authors: Guillaume
authors: G
authors: Gapihan
authors: INSERM, Paris France.|Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris France.
authors: Anne
authors: A
authors: Janin
authors: Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris France.|Department of Medical Oncology, Avicenne University Hospital (APHP- PRES Paris 13 University), Bobigny, France.
authors: Guilhem
authors: G
authors: Bousquet
authors: Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Maria Eugenia
authors: ME
authors: Riveiro
authors: Laboratory of Oncogenetics, Institut Curie, Hôpital René Huguenin, St-Cloud, France.
authors: Ivan
authors: I
authors: Bieche
authors: Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Sandrine
authors: S
authors: Faivre
authors: Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France.|INSERM, Paris France.
authors: Eric
authors: E
authors: Raymond
authors: AAREC Filia Research, Boulogne-Billancourt, France.|INSERM, Paris France.|Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris France.
authors: Armand
authors: A
authors: de Gramont
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077784:Axitinib; D000077210:Sunitinib
keywords: angiogenesis; differentiation; everolimus; renal cell carcinoma; sunitinib