Abstract
Glioblastomas are the most frequently diagnosed and one of the most lethal primary brain tumors, and one of their key features is a dysplastic vascular network. However, because the origin of the tumor blood vessels remains controversial, an optimal preclinical tumor model must be established to elucidate the tumor angiogenesis mechanism, especially the role of tumor cells themselves in angiogenesis. Therefore, shell-glioma cell (U118)-red fluorescent protein (RFP)/core-human umbilical vein endothelial cell (HUVEC)-green fluorescent protein (GFP) hydrogel microfibers were coaxially bioprinted. U118–RFP and HUVEC–GFP cells both exhibited good proliferation in a three-dimensional (3D) microenvironment. The secretability of both vascular endothelial growth factor A and basic fibroblast growth factor was remarkably enhanced when both types of cells were cocultured in 3D models. Moreover, U118 cells promoted the vascularization of the surrounding HUVECs by secreting vascular growth factors. More importantly, U118–HUVEC-fused cells were found in U118–RFP/HUVEC–GFP hydrogel microfibers. Most importantly, our results indicated that U118 cells can not only recruit the blood vessels of the surrounding host but also directly transdifferentiate into or fuse with endothelial cells to participate in tumor angiogenesis in vivo. The coaxially bioprinted U118–RFP/HUVEC–GFP hydrogel microfiber is a model suitable for mimicking the glioma microenvironment and for investigating tumor angiogenesis.
Highlights
Glioblastomas (GBMs) are the most diagnosed primary malignant central-nervous-system tumors in adults and have a very poor prognosis
Our results showed that U118–red fluorescent protein (RFP) and human umbilical vein endothelial cell (HUVEC)–green fluorescent protein (GFP) weakly secreted bFGF, their bFGF secretability was remarkably enhanced when both types of cells were cocultured in hydrogel microfibers possibly because when tumor and endothelial cells were cocultured in a 3D microenvironment, the paracrine and autocrine pathways of the cells stimulated the ability of both cells to secrete vascular growth factors (Zhou et al, 2021)
Our results showed that xenograft tumors contained a proportion of the tubule-like structures composed of endothelial/glial phenotypic cells, suggesting that U118 cells could directly transdifferentiate into or fuse with endothelial cells to participate in tumor angiogenesis
Summary
Glioblastomas (GBMs) are the most diagnosed primary malignant central-nervous-system tumors in adults and have a very poor prognosis. The traditional method of studying tumor angiogenesis in vitro mainly involves culturing tumor and endothelial cells in twodimensional (2D) Petri dishes, while in-vivo studies mainly rely on animal models (Verbridge et al, 2010). Cellular interactions with the 3D microenvironment are crucial for tumor growth and angiogenesis (Wang et al, 2018). Cytokines secreted by 2D-cultured cells diffuse into the medium and cannot reach an effective biological concentration, which is not conducive to cellular paracrine and autocrine functions and is different from the protein expression, cell-signal transduction, cell activity, and drug response of tumor cells in vivo (Wang et al, 2018; Yi et al, 2019). Over the past few decades, researchers have developed various 3D models for studying tumor angiogenesis (Wang et al, 2021)
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