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.
A chimeric plasmin‑resistant vascular endothelial growth factor (VEGF)165/VEGF183 (132-158) protein, named as VEGF183 (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 VEGF183, 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 VEGF183. 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 VEGF183 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 VEGF183‑overexpressing tumors demonstrated significantly lower vascular densities than those of VEGF165‑overexpressing tumors; however, VEGF183 tumors had a significantly enlarged vascular caliber. Conversely, cell wound healing experiments revealed that VEGF183‑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. [Corrected]
College of Life Science and Biotechnology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Hui-Yong
HY
Zhang
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Bing-Lin
BL
Fan
Department of Vasculocardiology, Xinxiang 371 Central Hospital, Xinxiang, Henan 453003, P.R. China.
Xin-Sheng
XS
Wu
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Ling-Min
LM
Mu
College of Life Science and Biotechnology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Wen-Feng
WF
Wang
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
Wu-Ling
WL
Zhu
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000473:pathology; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005341:Fibrinolysin