Overexpression of the chimeric plasmin-resistant VEGF165/VEGF183 (132-158) protein in murine breast cancer induces distinct vascular patterning adjacent to tumors and retarded tumor growth

• Published in: Molecular medicine reports Vol. 11; no. 2; pp. 1483 - 1489
• Main Authors: ZHANG, HUI-YONG, FAN, BING-LIN, WU, XIN-SHENG, MU, LING-MIN, WANG, WEN-FENG, ZHU, WU-LING
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.02.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Affinity; Amino Acid Sequence; Angiogenesis; Animals; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinogenesis; Cardiovascular disease; Cell Line, Tumor; Cell Movement; Cloning; Comparative analysis; Design; Development and progression; Disease Progression; Exons; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fibrinolysin - metabolism; Growth; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Microvessels - pathology; Neovascularization; Neovascularization, Pathologic; Peptides; Permeability; Physiological aspects; Plasmids; Plasmin; Proteins; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Skin; Transplantation, Homologous; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; vascular patterning; Wound healing; China; United States > US
• ISSN: 1791-2997; 1791-3004
• DOI: 10.3892/mmr.2014.2866

A chimeric plasmin-resistant vascular endothelial growth factor (VEGF)165/VEGF192 (132-158) protein, named as VEGF192 (according to the nomenclature of VEGF), designed by a previous study, was demonstrated to have an enhanced affinity for the extracellular matrix (ECM) amongst other bioactivities. However, it is now accepted that mutant VEGFs frequently demonstrate different angiogenic activities and produce different vascular patterning from the parental molecule. The present study hypothesized that VEGF192, due to its enhanced binding affinity to the ECM, would exhibit a different angiogenic activity and produce a different vascular patterning compared to those of VEGF165. Murine breast cancer EMT-6 cells were manipulated to stably overexpress VEGF165 or VEGF192. These cells were then inoculated intradermally into BALB/c mice in order to monitor the formation of vascular patterning in skin proximal to tumors. In vivo angiogenesis experiments revealed that overexpression of VEGF192 in murine breast cancer cells resulted in irregular, disorganized and dense vascular patterning as well as induced a significant inhibition of tumor growth compared with that of VEGF165. In addition, allograft tumor immunochemical assays of VEGF192-overexpressing tumors demonstrated significantly lower vascular densities than those of VEGF165-overexpressing tumors; however, VEGF192 tumors had a significantly enlarged vascular caliber. Conversely, cell wound healing experiments revealed that VEGF192-overexpressing EMT-6 cells had significantly decreased migration rates compared with those of VEGF165-overexpressing EMT-6 cells. In conclusion, the results of the present study supported the hypothesis that the altered ECM affinity of VEGF induced structural alterations to vasculature. In addition, these results provided a novel insight into VEGF design and indirect evidence for the function of exon 8 in VEGF.