PDGF-CC underlies resistance to VEGF-A inhibition and combinatorial targeting of both suppresses pathological angiogenesis more efficiently

Lei Zheng; Chen Zhao; Yuxiang Du; Xianchai Lin; Yida Jiang; Chunsik Lee; Geng Tian; Jia Mi; Xianglin Li; Qishan Chen; Zhimin Ye; Lijuan Huang; Shasha Wang; Xiangrong Ren; Liying Xing; Wei Chen; Delong Huang; Zhiqin Gao; Shuping Zhang; Weisi Lu; Zhongshu Tang; Bin Wang; Rong Ju; Xuri Li

doi:10.18632/oncotarget.12843

PDGF-CC underlies resistance to VEGF-A inhibition and combinatorial targeting of both suppresses pathological angiogenesis more efficiently

Oncotarget. 2016 Nov 22;7(47):77902-77915. doi: 10.18632/oncotarget.12843.

Authors

Lei Zheng^{1

2}, Chen Zhao³, Yuxiang Du², Xianchai Lin², Yida Jiang², Chunsik Lee², Geng Tian¹, Jia Mi¹, Xianglin Li¹, Qishan Chen², Zhimin Ye², Lijuan Huang², Shasha Wang², Xiangrong Ren², Liying Xing², Wei Chen², Delong Huang^{1

2}, Zhiqin Gao⁴, Shuping Zhang¹, Weisi Lu², Zhongshu Tang², Bin Wang⁵, Rong Ju², Xuri Li^{1

2}

Affiliations

¹ Center for Medical and Pharmaceutical Research, Binzhou Medical University, Yantai, Shandong, 264003, P. R. China.
² State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, P. R. China.
³ Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, P. R. China.
⁴ Department of Cell Biology, Weifang Medical University, Weifang, 261053 P. R. China.
⁵ Medical Imaging Institute, Shandong Province Characteristical Key Subject, Medical Imaging and Nuclear Medicine, Binzhou Medical University, Yantai, 264003 P. R. China.

Abstract

Anti-VEGF-A therapy has proven to be effective for many neovascular diseases. However, drug resistance to anti-VEGF-A treatment can develop. Also, not all patients with neovascular diseases are responsive to anti-VEGF-A treatment. The mechanisms underlying these important issues remain unclear. In this study, using different model systems, we found that inhibition of VEGF-A directly upregulated PDGF-CC and its receptors in multiple cell types in pathological angiogenesis in vitro and in vivo. Importantly, we further revealed that combinatorial targeting of VEGF-A and PDGF-CC suppressed pathological angiogenesis more efficiently than monotherapy. Given the potent angiogenic activity of PDGF-CC, our findings suggest that the development of resistance to anti-VEGF-A treatment may be caused by the compensatory upregulation of PDGF-CC, and combined inhibition of VEGF-A and PDGF-CC may have therapeutic advantages in treating neovascular diseases.

Keywords: PDGF-CC; VEGF-A; angiogenesis; drug resistance.

MeSH terms

Animals
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / pharmacology
Cells, Cultured
Choroidal Neovascularization / drug therapy*
Choroidal Neovascularization / metabolism*
Choroidal Neovascularization / pathology
Drug Resistance
Female
Humans
Lymphokines / biosynthesis
Lymphokines / metabolism*
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Inbred DBA
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Platelet-Derived Growth Factor / biosynthesis
Platelet-Derived Growth Factor / metabolism*
RAW 264.7 Cells
Retinal Pigment Epithelium / cytology
Retinal Pigment Epithelium / drug effects
Retinal Pigment Epithelium / metabolism
Signal Transduction
Up-Regulation
Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Vascular Endothelial Growth Factor A / immunology
Vascular Endothelial Growth Factor A / metabolism

Substances

Antibodies, Neutralizing
Lymphokines
Platelet-Derived Growth Factor
Vascular Endothelial Growth Factor A
platelet-derived growth factor C