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Cell Physiol Biochem. 2017;42(1):407-415. doi: 10.1159/000477485. Epub 2017 May 25.

Molecular Imaging of Inducible VEGF Expression and Tumor Progression in a Breast Cancer Model.

Liang L1,2,3, Yue Z1, Du W1, Li Y1, Tao H1, Wang D1, Wang R1, Huang Z1, He N1, Xie X4, Han Z2,3, Liu N1, Li Z1,5.

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Nankai University School of Medicine, Tianjin, China.
Beijing Institute of Health and Stem Cells, Health & Biotech Co., Beijing, China.
National Engineering Research Center of Cell Products, Tianjin, China.
Cells and Regenerative Medicine Laboratory, Beijing Institute of Transfusion Medicine, Beijing, China.
The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Science, Tianjin, China.



Tumor derived vascular endothelial growth factor (VEGF) can stimulate proliferation and migration of endothelial cells and recruit endothelial progenitor cells into tumors for vascular formation via a paracrine manner. Now increasing evidence suggests that VEGF also serves as an autocrine factor promoting cell survival and tumor angiogenesis. Real time visualization of VEGF activity in the early stages of tumor formation using molecular imaging will provide unprecedented insight into the biological processes of cancer.


The mouse breast cancer cell line 4T1 was transfected with an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF and renilla luciferase (Rluc). This was used to quantitatively image conditional switching of VEGF by bioluminescence imaging (BLI) under the control of systemic administration of doxycycline. Simultaneously, 4T1 cells were labelled with the double fusion reporter gene (Fluc-eGFP) to establish a breast cancer model.


We found that inducible VEGF could promote proliferation and attenuate apoptosis due to oxidative stress in an autocrine manner in vitro. In vivo studies revealed that induction of VEGF expression during early tumor development not only dramatically enhanced tumor growth but also increased tumor angiogenesis as visualized by BLI. Finally, immunohistochemistry staining confirmed that inducing VEGF expression promoted cell survival and tumor neovascularization.


Together the inducible bidirectional tetracycline (Bi-Tet) co-expression system combined with the dual bioluminescence imaging (BLI) system provides a platform to investigate a target gene's role in the pathologic process of cancer and facilitates noninvasive monitoring of biological responses in real time.


Angiogenesis; Bioluminescence; Breast cancer; Molecular imaging; Vascular endothelial growth factor (VEGF)

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