title: Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas.
abstract: Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulatevegfcgene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element-binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure.Cancer Res; 77(5); 1212-26. ©2017 AACR.
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.|Biomedical Department, Centre Scientifique de Monaco, Monaco, Principality of Monaco.
authors.forename: Sandy
authors.initials: S
authors.lastname: Giuliano
authors.affiliation: Central Laboratory of Pathology, Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Nice, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Ambrosetti
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.|Radiotherapy Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Claren
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.
authors.forename: Papa Diogop
authors.initials: PD
authors.lastname: Ndiaye
authors.affiliation: Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Michalis
authors.initials: M
authors.lastname: Mastri
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Walid
authors.initials: W
authors.lastname: Moghrabi
authors.affiliation: University of Bordeaux, INSERM U1029, Bordeaux, France.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Cooley
authors.affiliation: Statistics Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Ettaiche
authors.affiliation: Statistics Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chamorey
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Parola
authors.affiliation: Biomedical Department, Centre Scientifique de Monaco, Monaco, Principality of Monaco.
authors.forename: Valerie
authors.initials: V
authors.lastname: Vial
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.
authors.forename: Marilena
authors.initials: M
authors.lastname: Lupu-Plesu
authors.affiliation: Service d'Urologie, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Bernhard
authors.affiliation: Service d'Oncologie Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: Oncology Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Borchiellini
authors.affiliation: Oncology Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: University of Bordeaux, INSERM U1029, Bordeaux, France.
authors.forename: Andréas
authors.initials: A
authors.lastname: Bikfalvi
authors.affiliation: Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: John M
authors.initials: JM
authors.lastname: Ebos
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Khalid Saad
authors.initials: KS
authors.lastname: Khabar
authors.affiliation: Biomedical Department, Centre Scientifique de Monaco, Monaco, Principality of Monaco.
authors.forename: Renaud
authors.initials: R
authors.lastname: Grépin
authors.affiliation: University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France. gpages@unice.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology*; D000077210:Sunitinib; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042582:Vascular Endothelial Growth Factor C; D000077210:Sunitinib