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, vascular endothelial growth factor C (VEGFC).
In this study, we found that sunitinib can stimulate VEGFC gene transcription and increase VEGFC mRNA half-life. Additionally, sunitinib activated p38 MAP kinase, 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 treatment failure.
Cancer research. 2017 Jan 13 [Epub ahead of print]
Maeva Dufies, Sandy Giuliano, Damien Ambrosetti, Audrey Claren, Papa Diogop Ndiaye, Michalis Mastri, Walid Moghrabi, Lindsay S Cooley, Marc Ettaiche, Emmanuel Chamorey, Julien Parola, Valerie Vial, Marilena Lupu-Plesu, Jean-Christophe Bernhard, Alain Ravaud, Delphine Borchiellini, Jean Marc Ferrero, Andreas Bikfalvi, John M L Ebos, Khalid S A Khabar, Renaud Grepin, Gilles Pagès
Institute for Research on Cancer and Aging of Nice, University Nice-Sophia Antipolis CNRS UMR 7284; INSERM U1081., Centre A. Lacassagne, IRCAN, University of Nice-Sophia Antipolis., Department of Pathology, Pasteur Hospital., Institute for Research on Cancer and Aging of Nice / Radiotherapy department, University Nice-Sophia Antipolis CNRS UMR 7284; INSERM U1081 / Centre Antoine Lacassagne., Genitourinary Section, Roswell Park Cancer Institute., Molecular BioMedicine Program, King Faisal Specialist Hospital and Research Centre., INSERM U1029, Université Bordeaux., Statistic department, Centre Antoine Lacassagne., Statistics, Centre Antoine Lacassagne., Biomedical Department, Centre Scientifique de Monaco., Department of Urology, CHU Bordeaux., Medical Oncology, Hopital Saint-Andre, University Hospital., Clinical research department, Centre Antoine Lacassagne., Medical Oncology Department, Anticancer Center, Centre Antoine-Lacassagne., Inserm U1029-LAMC, INSERM and University Bordeaux., Cancer Genetics; Medicine, Roswell Park Cancer Institute., Institute for Research on Cancer and Aging of Nice, University Nice-Sophia Antipolis CNRS UMR 7284; INSERM U1081 .