title: Tumor resistance to anti-VEGF therapy through up-regulation of VEGF-C expression.
abstract: Increasing evidence has indicated that prolonged use of anti-VEGF (vascular endothelial growth factor) agents for cancer therapy promotes tumor resistance. To gain insight into the molecular mechanism underlying resistance to anti-VEGF therapy, we developed a mouse Lewis lung carcinoma (LLC) cell line that is resistant to treatment with a potent VEGF inhibitor, VEGF-Trap, through repeated in vivo selection. We compared the transcriptome profiles of resistant and non-resistant tumor cells using RNA-seq analysis. VEGF-C was significantly up-regulated in resistant tumor cells, as determined by quantitative real-time PCR and immunohistochemical analyses. Inhibition of VEGF-C in resistant cells suppressed endothelial cell migration in vitro and partially restored sensitivity to VEGF-Trap treatment in vivo. Our findings indicate that tumors may develop resistance to anti-VEGF therapy by activating the VEGF-C pathway.
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Dong
authors: D
authors: Li
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Kun
authors: K
authors: Xie
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Guitao
authors: G
authors: Ding
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Jie
authors: J
authors: Li
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Kaiming
authors: K
authors: Chen
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Hongwen
authors: H
authors: Li
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Jie
authors: J
authors: Qian
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Cizhong
authors: C
authors: Jiang
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: jfang@tongji.edu.cn.
authors: Jianmin
authors: J
authors: Fang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Angiogenesis; Animal model; Drug resistance; Lung carcinoma; RNA-seq; VEGF