Supplemental Figure S6 from Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas

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posted on 2023-03-31, 01:00 authored by 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, Andréas Bikfalvi, John M. Ebos, Khalid Saad Khabar, Renaud Grépin, Gilles Pagès

Supplementary Figure S6. Overexpression of VEGFC correlated with reduced overall survival of RCC patients. A, Kaplan-Meier survival curves of metastatic (M1) RCC patients with high or low VEGFC mRNA expression. These results are in whole or in part based upon data generated by the TCGA Research Network. B, Proportion of groups of patients with VEGFC low or high and its correlation with metastatic stage (M1). Statistical significance (Khi2 test) is indicated. C, Multivariate analysis for VEGFC, stage 3/4, metastatic stage (M1) and lymph node metastatic stage (N1). Statistical significance (p values) and the risk ratio are indicated.

Funding

U.S. Department of Defense

History

ARTICLE 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 stimulate vegfc gene 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.