Aggregative Perivascular Tumor Cell Growth Pattern of Primary Central Nervous System Lymphomas Is Associated with Hypoxia-Related Endoplasmic Reticulum Stress

Miaoxia He; Weiwei Zhang; Jianjun Wang; Lei Gao; Lijuan Jiao; Laixing Wang; Jianmin Zheng; Zailong Cai; Jianmin Yang

doi:10.7150/jca.54952

Aggregative Perivascular Tumor Cell Growth Pattern of Primary Central Nervous System Lymphomas Is Associated with Hypoxia-Related Endoplasmic Reticulum Stress

J Cancer. 2021 May 5;12(13):3841-3852. doi: 10.7150/jca.54952. eCollection 2021.

Authors

Miaoxia He¹, Weiwei Zhang², Jianjun Wang¹, Lei Gao³, Lijuan Jiao¹, Laixing Wang⁴, Jianmin Zheng¹, Zailong Cai⁵, Jianmin Yang³

Affiliations

¹ Department of pathology, Changhai Hospital, Shanghai 200433, China.
² Department of Experimental Diagnose, Changhai Hospital, Shanghai 200433, China.
³ Department of Hematology, Changhai Hospital, Shanghai 200433, China.
⁴ Department of Neurosurgery, Changhai Hospital, Shanghai 200433, China.
⁵ Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, 200433 China.

Abstract

Primary central nervous system lymphomas (PCNSLs) often present a unique histopathological feature of aggregative perivascular tumor cells (APVT). Our previous studies showed that patients of PCNSL with APVTs exhibited poor long-term outcomes and increased expression of the endoplasmic reticulum stress (ERS) factor X-box-binding protein (XBP1). However, very little is known about molecular mechanism of the APVT formation in PCNSLs. The aim of this study is to determine if hypoxia-induced ERS is related to the APVT formation in PCNSLs. In this study, cell culture was used to observe the interplay between diffuse large B cell lymphoma (DLBCL) tumor cells and human brain microvascular endothelial cells (HBMECs) in different oxygen conditions. The expression of XBP1, CXCR and CD44 was manipulated by molecular cloning and siRNA technology. Mouse in vivo experiments and clinical studies were conducted to confirm our hypothesis. Our results showed that activated B-cell type-DLBCL cells easily migrated and invaded, and expressed high levels of XBP1 and stromal molecules CXCR4 and CD44 during hypoxia-induced ERS and dithiothreitol unfolded protein response (UPR). The gene upregulation (using overexpression vector) and downregulation (siRNA gene knock-out) in cultured cells and in mouse models further confirmed a close relation of the expression of XBP1, CXCR4, and CD44 with APVT formation, which is coincided with our clinical observation that increased expression of XBP1, CXCR4, and CD44 in the APVT cells in PCNSLs were associated with poor clinical outcomes. The results suggest that hypoxia-induced ERS and UPR might be associated with APVTs formation in PCNSL and its poor clinical outcomes. The results will help us better understand the progression of PCNSL with APVTs feature in daily pathological work and could be valuable for future target treatment of PCNSLs.

Keywords: APVT formation; Primary central nervous system lymphomas; clinical outcome; endoplasmic reticulum stress and signal transduction.; hypoxia.