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

doi:10.1039/D0BM02107E

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

Yaqi Qiu,

‡^a Ning Wang,‡^ab Tingting Guo,‡^a Shoupei Liu,^a Xianglian Tang,^ab Zhiyong Zhong,^ab Qicong Chen,

^ab Haibin Wu,^a Xiajing Li,^c Jue Wang,^a Shuai Zhang,^d Yimeng Ou,^e Bailin Wang,^f Keqiang Ma,^g Weili Gu,*^d Jie Cao,*^h Honglin Chen*^aijkl and Yuyou Duan*^aijkl

Author affiliations

* Corresponding authors

^a Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China
E-mail: yuyouduan@scut.edu.cn, chenhl@scut.edu.cn
Tel: +86 20 3939 0970

^b School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 510006, P. R. China

^c Department of Blood Transfusion, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, P. R. China

^d Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, P. R. China
E-mail: lili-6423@163.com
Tel: +86 20 8104 8281

^e Department of General Surgery, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, P. R. China

^f Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, P. R. China

^g Department of Hepatobiliary Pancreatic Surgery, Huadu District People's Hospital of Guangzhou, Guangzhou, P. R. China

^h Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, P. R. China
E-mail: eycaojie@scut.edu.cn
Tel: +86 20 8104 8181

ⁱ National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China

^j Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, P. R. China

^k Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P. R. China

^l Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China

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.

Biomaterials Science

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

Abstract

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

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