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Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma

 Kyung Seok Han  ;  Peter A. Raven  ;  Sebastian Frees  ;  Kilian Gust  ;  Ladan Fazli  ;  Susan Ettinger  ;  Sung Joon Hong  ;  Cristian Kollmannsberger  ;  Martin E. Gleave  ;  Alan I. So 
 NEOPLASIA, Vol.17(11) : 805-816, 2015 
Journal Title
Issue Date
Angiogenesis Inhibitors/administration & dosage ; Angiogenesis Inhibitors/metabolism* ; Animals ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/metabolism* ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/physiology ; Dose-Response Relationship, Drug ; Drug Delivery Systems*/methods ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/physiology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Female ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Indoles/administration & dosage ; Indoles/metabolism* ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/metabolism* ; Mice ; Mice, Nude ; Pyrroles/administration & dosage ; Pyrroles/metabolism* ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Vascular Endothelial Growth Factor A/metabolism* ; Xenograft Model Antitumor Assays/methods
Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.
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1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Han, Kyung Seok(한경석)
Hong, Sung Joon(홍성준) ORCID logo https://orcid.org/0000-0001-9869-065X
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