title: Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma.
abstract: 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.
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung Seok
authors.initials: KS
authors.lastname: Han
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Raven
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Frees
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Kilian
authors.initials: K
authors.lastname: Gust
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Ettinger
authors.affiliation: Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Hong
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Cristian
authors.initials: C
authors.lastname: Kollmannsberger
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada. Electronic address: dralanso@mail.ubc.ca.
authors.forename: Alan I
authors.initials: AI
authors.lastname: So
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib