Abstract
Angiogenesis is critical for local tumor growth. This study aimed to develop a three-dimensional two-layer co-culture system to investigate effects of cancer cells on the growth of endothelial cells (ECs). Poly(ε-caprolactone) (PCL) nanofibrous membranes were generated via electrospinning of PCL in chloroform (C-PCL-M) and chloroform and dimethylformamide (C/DMF-PCL-M). We assembled a two-layer co-culture system using C-PCL-M and C/DMF-PCL-M for EC growth in the upper layer with co-cultured cancer cells in the lower layer. In the absence of vascular endothelial growth factor (VEGF), growth of bEND.3 ECs decreased on C/DMF-PCL-M but not on C-PCL-M with time. Growth of bEND.3 cells on C/DMF-PCL-M was enhanced through co-culturing of CT26 cancer cells and enhanced growth of bEND.3 cells was abrogated with anti-VEGF antibodies and sorafenib. However, EA.hy926 ECs displayed steady growth and proliferation on C/DMF-PCL-M, and their growth was not further increased through co-culturing of cancer cells. Moreover, chemical hypoxia in CT26 cancer cells upon treatment with CoCl2 enhanced the growth of co-cultured bEND.3 cells in the two-layer system. Thus, EC growth on the nanofibrous scaffold is dependent on the types of ECs and composition of nanofibers and this co-culture system can be used to analyze EC growth induced by cancer cells.
Highlights
Neovasculogenesis occurs after endothelial cell (EC) proliferation and migration [1,2]
PCL nanofibrous membranes were generated via electrospinning of PCL in chloroform (C-PCL-M) and chloroform and dimethylformamide (C/DMF-PCL-M) [28]
We investigated the effects of solvent on the morphology and size of electrospun fibers
Summary
Neovasculogenesis occurs after endothelial cell (EC) proliferation and migration [1,2]. Angiogenesis is critical for local growth and metastasis of malignant tumors, and the tumor vasculature is structurally abnormal [3]. Tumors located > 100–200 μm from neighboring blood capillaries often encounter hypoxic conditions. Hypoxia is one of the primary factors inducing tumor angiogenesis, upregulating vascular endothelial growth factor (VEGF) in tumor cells under hypoxia [4,5]. Exposure to hypoxia significantly upregulates hypoxia-inducible factor (HIF)-1α to transcriptionally regulate VEGF [6]. CoCl2 treatment of cells in vitro reportedly induces cellular changes similar to those observed upon hypoxia condition [7]. CoCl2 mimics hypoxia, at least in part, by occupying the Von Hippel–Lindau-binding domain of HIF-1α, preventing the degradation of HIF-1α [8], there are certain differences between physiological hypoxia and CoCl2-induced hypoxia [9]
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