Establishment of a 3D model of tumor-driven angiogenesis to study the effects of anti-angiogenic drugs on pericyte recruitment

Yaqi Qiu, Ning Wang, Tingting Guo, Shoupei Liu, Xianglian Tang, Zhiyong Zhong, Qicong Chen, Haibin Wu, Xiajing Li, Jue Wang, Shuai Zhang, Yimeng Ou, Bailin Wang, Keqiang Ma, Weili Gu, Jie Cao, Honglin Chen, Yuyou Duan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hepatocellular carcinoma (HCC), as a well-vascularized tumor, has attracted increasing attention in antiangiogenic therapies. Notably, emerging studies reveal that the long-term administration of antiangiogenic drugs induces hypoxia in tumors. Pericytes, which play a vital role in vascular stabilization and maturation, have been documented to be associated with antiangiogenic drug-induced tumor hypoxia. However, the role of antiangiogenic agents in regulating pericyte behavior still remains elusive. In this study, by using immunostaining analysis, we first demonstrated that tumors obtained from HCC patients were highly angiogenic, in which vessels were irregularly covered by pericytes. Therefore, we established a new 3D model of tumor-driven angiogenesis by culturing endothelial cells, pericytes, cancer stem cells (CSCs) and mesenchymal stem cells (MSCs) with microcarriers in order to investigate the effects and mechanisms exerted by antiangiogenic agents on pericyte recruitment during tumor angiogenesis. Interestingly, microcarriers, as supporting matrices, enhanced the interactions between tumor cells and the extracellular matrix (ECM), promoted malignancy of tumor cells and increased tumor angiogenesis within the 3D model, as determined by qRT-PCR and immunostaining. More importantly, we showed that zoledronic acid (ZA) reversed the inhibited pericyte recruitment, which was induced by sorafenib (Sora) treatment, through fostering the expression and activation of ErbB1/ErbB2 and PDGFR-β in pericytes, in both an in vitro 3D model and an in vivo xenograft HCC mouse model. Hence, our model provides a more pathophysiologically relevant platform for the assessment of therapeutic effects of antiangiogenic compounds and identification of novel pharmacological targets, which might efficiently improve the benefits of antiangiogenic treatment for HCC patients.

Original languageEnglish (US)
Pages (from-to)6064-6085
Number of pages22
JournalBiomaterials Science
Volume9
Issue number18
DOIs
StatePublished - Sep 21 2021
Externally publishedYes

ASJC Scopus subject areas

  • Biomedical Engineering
  • Materials Science(all)

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